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Showing papers in "Journal of Computational Chemistry in 2010"


Journal ArticleDOI
TL;DR: The Cholesky decomposition method applied to some quantum chemical methods is described, and the ElectroStatic Potential Fitted scheme, a version of a quantum mechanics/molecular mechanics hybrid method implemented in MOLCAS, is described and discussed.
Abstract: Some of the new unique features of the MOLCAS quantum chemistry package version 7 are presented inthis report. In particular, the Cholesky decomposition method applied to some quantum chemical methods is described. This approach is used both in the context of a straight forward approximation of the two-electron integrals and in the generation of so-called auxiliary basis sets. The article describes how the method is implemented for most known wave functions models: self-consistent field, density functional theory, 2nd order perturbation theory, complete-active space self-consistent field multiconfigurational reference 2nd order perturbation theory, and coupled-cluster methods. The report further elaborates on the implementation of a restricted-active space self-consistent field reference function in conjunction with 2nd order perturbation theory. The average atomic natural orbital basis for relativistic calculations, covering the whole periodic table, are described and associated unique properties are demonstrated. Furthermore, the use of the arbitrary order Douglas-Kroll-Hess transformation for one-component relativistic calculations and its implementation are discussed. This section especially focuses on the implementation of the so-called picture-change-free atomic orbital property integrals. Moreover, the ElectroStatic Potential Fitted scheme, a version of a quantum mechanics/molecular mechanics hybrid method implemented in MOLCAS, is described and discussed. Finally, the report discusses the use of the MOLCAS package for advanced studies of photo chemical phenomena and the usefulness of the algorithms for constrained geometry optimization in MOLCAS in association with such studies. (c) 2009 Wiley Periodicals, Inc. J Corn put Chem 31: 224-247, 2010

1,492 citations


Journal ArticleDOI
TL;DR: To efficiently insert a protein into an equilibrated and fully hydrated membrane with minimal membrane perturbation, g_membed is presented, which is part of the Gromacs suite of programs and very practical for use in scripting and high‐throughput molecular dynamics simulations.
Abstract: To efficiently insert a protein into an equilibrated and fully hydrated membrane with minimal membrane perturbation we present a computational tool, called g_membed, which is part of the Gromacs suite of programs. The input consists of an equilibrated membrane system, either flat or curved, and a protein structure in the right position and orientation with respect to the lipid bilayer. g_membed first decreases the width of the protein in the xy-plane and removes all molecules (generally lipids and waters) that overlap with the narrowed protein. Then the protein is grown back to its full size in a short molecular dynamics simulation (typically 1000 steps), thereby pushing the lipids away to optimally accommodate the protein in the membrane. After embedding the protein in the membrane, both the lipid properties and the hydration layer are still close to equilibrium. Thus, only a short equilibration run (less then 1 ns in the cases tested) is required to re-equilibrate the membrane. Its simplicity makes g_membed very practical for use in scripting and high-throughput molecular dynamics simulations.

357 citations


Journal ArticleDOI
TL;DR: The timescale on which membrane sealing was observed using this model appears closer to the timescales for membrane resealing suggested by electroporation experiments than previous simulations using existing models.
Abstract: A new force field for the simulation of dipalmitoylphosphatidylcholine (DPPC) in the liquid-crystalline, fluid phase at zero surface tension is presented. The structure of the bilayer with the area per lipid (0.629 nm(2); experiment 0.629-0.64 nm(2)), the volume per lipid (1.226 nm(3); experiment 1.229-1.232 nm(3)), and the ordering of the palmitoyl chains (order parameters) are all in very good agreement with experiment. Experimental electron density profiles are well reproduced in particular with regard to the penetration of water into the bilayer. The force field was further validated by simulating the spontaneous assembly of DPPC into a bilayer in water. Notably, the timescale on which membrane sealing was observed using this model appears closer to the timescales for membrane resealing suggested by electroporation experiments than previous simulations using existing models.

317 citations


Journal ArticleDOI
Xun Li1, Yan Li1, Tiejun Cheng1, Zhihai Liu1, Renxiao Wang1 
TL;DR: An extensive evaluation of four popular commercial molecular docking programs, including Glide, GOLD, LigandFit, and Surflex, indicates that these programs are less capable to handle really flexible ligands and relatively flat binding sites, and they have different preferences to hydrophilic/hydrophobic binding sites.
Abstract: Many molecular docking programs are available nowadays, and thus it is of great practical value to evaluate and compare their performance. We have conducted an extensive evaluation of four popular commercial molecular docking programs, including Glide, GOLD, LigandFit, and Surflex. Our test set consists of 195 protein-ligand complexes with high-resolution crystal structures (resolution

289 citations


Journal ArticleDOI
TL;DR: A large‐scale docking experiment was performed to assess the extent of misrepresentation of natural (in‐solvent) protein dimers by crystal packing, and the failure rate of docking may be quantitatively interpreted if both calculation errors and misrepresentation effects are taken into account.
Abstract: The assumption that crystal contacts reflect natural macromolecular interactions makes a basis for many studies in structural biology. However, the crystal state may correspond to a global minimum of free energy where biologically relevant interactions are sacrificed in favor to unspecific contacts. A large-scale docking experiment was performed to assess the extent of misrepresentation of natural (in-solvent) protein dimers by crystal packing. As found, the failure rate of docking may be quantitatively interpreted if both calculation errors and misrepresentation effects are taken into account. The failure rate analysis is based on the assumption that crystal structures reflect thermodynamic equilibrium between different dimeric configurations. The analysis gives an estimate of misrepresentation probability, which suggests that weakly bound complexes with K(D) > or = 100 microM (some 20% of all dimers in the PDB) have higher than 50% chances to be misrepresented by crystals. The developed theoretical framework is applicable in other studies, where experimental results may be viewed as snapshots of systems in thermodynamic equilibrium.

277 citations


Journal ArticleDOI
TL;DR: The graphical user interface (GUI) TmoleX allows users to execute the complete workflow of a quantum chemical investigation from the initial building of a structure to the visualization of the results in a user friendly graphical front end.
Abstract: We herein present the graphical user interface (GUI) TmoleX for the quantum chemical program package TURBOMOLE. TmoleX allows users to execute the complete workflow of a quantum chemical investigation from the initial building of a structure to the visualization of the results in a user friendly graphical front end. The purpose of TmoleX is to make TURBOMOLE easy to use and to provide a high degree of flexibility. Hence, it should be a valuable tool for most users from beginners to experts. The program is developed in Java and runs on Linux, Windows, and Mac platforms. It can be used to run calculations on local desktops as well as on remote computers.

249 citations


Journal ArticleDOI
TL;DR: An algorithm to reconstruct atomistic structures from their corresponding coarse‐grained (CG) representations and its implementation into the freely available molecular dynamics (MD) program package GROMACS is presented.
Abstract: We present an algorithm to reconstruct atomistic structures from their corresponding coarse-grained (CG) representations and its implementation into the freely available molecular dynamics (MD) program package GROMACS. The central part of the algorithm is a simulated annealing MD simulation in which the CG and atomistic structures are coupled via restraints. A number of examples demonstrate the application of the reconstruction procedure to obtain low-energy atomistic structural ensembles from their CO counterparts. We reconstructed individual molecules in vacuo (NCQ tripeptide, dipalmitoylphosphatidylcholine, and cholesterol), bulk water, and a WALP transmembrane peptide embedded in a solvated lipid bilayer. The first examples serve to optimize the parameters for the reconstruction procedure, whereas the latter examples illustrate the applicability to condensed-phase biomolecular systems. (C) 2010 Wiley Periodicals, Inc. J Comput Chem 31 : 1333-1343, 2010

186 citations


Journal ArticleDOI
TL;DR: An excited‐state proton transfer process, induced by both intermolecular and intramolecular hydrogen‐bonding interactions, is proposed to account for the fluorescence sensing mechanism of a fluoride chemosensor, phenyl‐1H‐anthra(1,2‐d)imidazole‐6,11‐dione.
Abstract: An excited-state proton transfer (espt) process, induced by both intermolecular and intramolecular hydrogen-bonding interactions, is proposed to account for the fluorescence sensing mechanism of a fluoride chemosensor, phenyl-1h-anthra(1,2-d)imidazole-6,11-dione. the time-dependent density functional theory (td-dft) method has been applied to investigate the different electronic states. the present theoretical study of this chemosensor, as well as its anion and fluoride complex, has been conducted with a view to monitoring its structural and photophysical properties. the proton of the chemosensor can shift to fluoride in the ground state but transfers from the proton donor (nh group) to a proton acceptor (neighboring carbonyl group) in the first singlet excited state. this may explain the observed red shifts in the fluorescence spectra in the relevant fluorescent sensing mechanism. (c) 2010 wiley periodicals, inc. j comput chem 31: 1759-1765, 2010

164 citations


Journal ArticleDOI
TL;DR: A Lamarckian genetic algorithm (LGA) variant for flexible ligand‐receptor docking which allows to handle a large number of degrees of freedom and may be used to dock ligands with many rotatable bonds with high efficiency.
Abstract: We present a Lamarckian genetic algorithm (LGA) variant for flexible ligand-receptor docking which allows to handle a large number of degrees of freedom. Our hybrid method combines a multi-deme LGA with a recently published gradient-based method for local optimization of molecular complexes. We compared the performance of our new hybrid method to two non gradient-based search heuristics on the Astex diverse set for flexible ligand-receptor docking. Our results show that the novel approach is clearly superior to other LGAs employing a stochastic optimization method. The new algorithm features a shorter run time and gives substantially better results, especially with increasing complexity of the ligands. Thus, it may be used to dock ligands with many rotatable bonds with high efficiency.

161 citations


Journal ArticleDOI
TL;DR: Analysis of the molecular geometries and interaction energies at density functional theory (DFT), MP2, CCSD methods and CCST(T) single point level reveal that MP2 is the best overall performer for noncovalent interactions giving accuracy close to C CSD method.
Abstract: A comparison of the performance of various density functional methods including long-range corrected and dispersion corrected methods [MPW1PW91, B3LYP, B3PW91, B97-D, B1B95, MPWB1K, M06-2X, SVWN5, ωB97XD, long-range correction (LC)-ωPBE, and CAM-B3LYP using 6-31+G(d,p) basis set] in the study of CH···π, OH···π, and NH···π interactions were done using weak complexes of neutral (A) and cationic (A+) forms of alanine with benzene by taking the Moller–Plesset (MP2)/6-31+G(d,p) results as the reference. Further, the binding energies of the neutral alanine–benzene complexes were assessed at coupled cluster (CCSD)/6-31G(d,p) method. Analysis of the molecular geometries and interaction energies at density functional theory (DFT), MP2, CCSD methods and CCSD(T) single point level reveal that MP2 is the best overall performer for noncovalent interactions giving accuracy close to CCSD method. MPWB1K fared better in interaction energy calculations than other DFT methods. In the case of M06-2X, SVWN5, and the dispersion corrected B97-D, the interaction energies are significantly overrated for neutral systems compared to other methods. However, for cationic systems, B97-D yields structures and interaction energies similar to MP2 and MPWB1K methods. Among the long-range corrected methods, LC-ωPBE and CAM-B3LYP methods show close agreement with MP2 values while ωB97XD energies are notably higher than MP2 values. © 2010 Wiley Periodicals, Inc. J Comput Chem 2010

118 citations


Journal ArticleDOI
TL;DR: A simple and robust algorithm to rapidly determine the optimal rotation using a Newton‐Raphson quaternion‐based method and an adjoint matrix is presented, which is at least an order of magnitude more efficient than conventional inversion/decomposition methods.
Abstract: Finding the rotational matrix that minimizes the sum of squared deviations between two vectors is an important problem in bioinformatics and crystallography. Traditional algorithms involve the inversion or decomposition of a 3 × 3 or 4 × 4 matrix, which can be computationally expensive and numerically unstable in certain cases. Here, we present a simple and robust algorithm to rapidly determine the optimal rotation using a Newton-Raphson quaternion-based method and an adjoint matrix. Our method is at least an order of magnitude more efficient than conventional inversion/decomposition methods, and it should be particularly useful for high-throughput analyses of molecular conformations. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010

Journal ArticleDOI
TL;DR: This approach, which bears some analogies with adaptive umbrella sampling and metadynamics (but within a very distinct implementation), is shown to be efficient, robust, versatile and robust to the details of the build‐up protocol.
Abstract: A method is proposed to combine the local elevation (LE) conformational searching and the umbrella sampling (US) conformational sampling approaches into a single local elevation umbrella sampling (LEUS) scheme for (explicit-solvent) molecular dynamics (MD) simulations. In this approach, an initial (relatively short) LE build-up (searching) phase is used to construct an optimized biasing potential within a subspace of conformationally relevant degrees of freedom, that is then used in a (comparatively longer) US sampling phase. This scheme dramatically enhances (in comparison with plain MD) the sampling power of MD simulations, taking advantage of the fact that the preoptimized biasing potential represents a reasonable approximation to the negative of the free energy surface in the considered conformational subspace. The method is applied to the calculation of the relative free energies of β-D-glucopyranose ring conformers in water (within the GROMOS 45A4 force field). Different schemes to assign sampled conformational regions to distinct states are also compared. This approach, which bears some analogies with adaptive umbrella sampling and metadynamics (but within a very distinct implementation), is shown to be: (i) efficient (nearly all the computational effort is invested in the actual sampling phase rather than in searching and equilibration); (ii) robust (the method is only weakly sensitive to the details of the build-up protocol, even for relatively short build-up times); (iii) versatile (a LEUS biasing potential database could easily be preoptimized for small molecules and assembled on a fragment basis for larger ones). © 2009 Wiley Periodicals, Inc. J Comput Chem 2010

Journal ArticleDOI
TL;DR: Simulaid performs a large number of simulation‐related tasks: interconversion and modification of structure and trajectory files, optimization of orientation, and a large variety of analysis functions.
Abstract: Simulaid performs a large number of simulation-related tasks: interconversion and modification of structure and trajectory files, optimization of orientation, and a large variety of analysis functions. The program can handle structures in PDB (Berman et al., Nucleic Acids Res 2000, 28, 235), Charmm (Brooks et al., J Comput Chem 4, 187) CRD, Amber (Case et al.), Macromodel (Mohamadi et al., J Comput Chem 1990, 11, 440), Gromos/Gromacs (Hess et al.), InsightII (InsightII. Accelrys Inc.: San Diego, 2005), Grasp (Nicholls et al., Proteins: Struct Funct Genet 1991, 11, 281) .crg, Tripos (Tripos International, S. H. R., St. Louis, MO) .mol2 (input only), and in the MMC (Mezei, M.; MMC: Monte Carlo program for molecular assemblies. Available at: http://inka.mssm.edu/~mezei/mmc) formats; and trajectories in the formats of Charmm, Amber, Macromodel, and MMC. Analysis features include (but are not limited to): (1) simple distance calculations and hydrogen-bond analysis, (2) calculation of 2-D RMSD maps (produced both as text file with the data and as a color-coded matrix) and cross RMSD maps between trajectories, (3) clustering based on RMSD maps, (4) analysis of torsion angles, Ramachandran (Ramachandran and Sasiskharan, Adv Protein Chem 1968, 23, 283) angles, proline kink (Visiers et al., Protein Eng 2000, 13, 603) angles, pseudorotational (Altona and Sundaralingam, J Am Chem Soc 1972, 94, 8205; Cremer and Pople, J Am Chem Soc 1975, 97, 1354) angles, and (5) analysis based on circular variance (Mezei, J Mol Graphics Model 2003, 21, 463). Torsion angle evolutions are presented in dial plots (Ravishanker et al., J Biomol Struct Dyn 1989, 6, 669). Several of these features are unique to Simulaid.

Journal ArticleDOI
TL;DR: This study systematically analyzed the CPU time and memory usage of five commonly used finite‐difference solvers with a large and diversified set of biomolecular structures and shows that modified incomplete Cholesky conjugate gradient and geometric multigrid are the most efficient in the diversified test set.
Abstract: CPU time and memory usage are two vital issues that any numerical solvers for the Poisson–Boltzmann equation have to face in biomolecular applications. In this study, we systematically analyzed the CPU time and memory usage of five commonly used finite-difference solvers with a large and diversified set of biomolecular structures. Our comparative analysis shows that modified incomplete Cholesky conjugate gradient and geometric multigrid are the most efficient in the diversified test set. For the two efficient solvers, our test shows that their CPU times increase approximately linearly with the numbers of grids. Their CPU times also increase almost linearly with the negative logarithm of the convergence criterion at very similar rate. Our comparison further shows that geometric multigrid performs better in the large set of tested biomolecules. However, modified incomplete Cholesky conjugate gradient is superior to geometric multigrid in molecular dynamics simulations of tested molecules. We also investigated other significant components in numerical solutions of the Poisson–Boltzmann equation. It turns out that the time-limiting step is the free boundary condition setup for the linear systems for the selected proteins if the electrostatic focusing is not used. Thus, development of future numerical solvers for the Poisson–Boltzmann equation should balance all aspects of the numerical procedures in realistic biomolecular applications. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010

Journal ArticleDOI
TL;DR: The structural and mechanistic observations based on the all-atom molecular dynamics simulations agree with the recent NMR experiments and provide the driving force and structural origin for the As42 aggregation process to cause AD.
Abstract: Extracellular deposition of amyloid-beta (Aβ) protein, a fragment of membrane glycoprotein called β-amyloid precursor transmembrane protein (βAPP), is the major characteristic for the Alzheimer's disease (AD). However, the structural and mechanistic information of forming Aβ protein aggregates in a lag phase in cell exterior has been still limited. Here, we have performed multiple all-atom molecular dynamics simulations for physiological 42-residue amyloid-beta protein (Aβ42) in explicit water to characterize most plausible aggregation-prone structure (APS) for the monomer and the very early conformational transitions for Aβ42 protein misfolding process in a lag phase. Monitoring the early sequential conformational transitions of Aβ42 misfolding in water, the APS for Aβ42 monomer is characterized by the observed correlation between the nonlocal backbone H-bond formation and the hydrophobic side-chain exposure. Characteristics on the nature of the APS of Aβ42 allow us to provide new insight into the higher aggregation propensity of Aβ42 over Aβ40, which is in agreement with the experiments. On the basis of the structural features of APS, we propose a plausible aggregation mechanism from APS of Aβ42 to form fibril. The structural and mechanistic observations based on these simulations agree with the recent NMR experiments and provide the driving force and structural origin for the Aβ42 aggregation process to cause AD.

Journal ArticleDOI
TL;DR: A systematic study of the reaction mechanism of the histone lysine methyltransferase (HKMT) SET7/9 enzyme, which catalyzes the methylation of the N‐terminal histone tail of the chromatin structure.
Abstract: Quantum chemical cluster models of enzyme active sites are today an important and powerful tool in the study of various aspects of enzymatic reactivity. This methodology has been applied to a wide ...

Journal ArticleDOI
TL;DR: MTA has been interfaced with recently developed efficient Møller‐Plesset second order perturbation theory (MP2) codes viz.
Abstract: Many Divide-and-Conquer based approaches are being developed to overcome the high scaling problem of the ab initio methods. In this work, one such method, Molecular Tailoring Approach (MTA) has been interfaced with recently developed efficient Moller-Plesset second order perturbation theory (MP2) codes viz. IMS-MP2 and RI-MP2 to reap the advantage of both. An external driver script is developed for implementing MTA at the front-end and the MP2 codes at the back-end. The present version of the driver script is written only for a single point energy evaluation of a molecular system at a fixed geometry. The performance of these newly developed MTA-IMS-MP2 and MTA-RI-MP2 codes is extensively benchmarked for a variety of molecular systems vis-a-vis the corresponding actual runs. In addition to this, the performance of these programs is also critically compared with Fragment Molecular Orbital (FMO), another popular fragment-based method. It is observed that FMO2/2 is superior to FMO3/2 and MTA with respect to time advantage; however, the errors of FMO2 are much beyond chemical accuracy. However, FMO3/2 is a highly accurate method for biological systems but is unsuccessful in case of water clusters. MTA produces estimates with errors within 1 kcal/mol uniformly for all systems with reasonable time advantage. Analysis carried out employing various basis sets shows that FMO gives its optimum performance only for basis sets, which does not include diffuse functions. On the contrary, MTA performance is found to be similar for any basis set used.

Journal ArticleDOI
TL;DR: A unique binding mode for quinone derivatives and 9‐aminoacridine derivatives, at the FAD binding domain is reported, which is likely to have biological significance and possible mode of inhibition by quin one derivatives, which binds to FADbinding domain, along with other compounds are discussed.
Abstract: Visceral leishmaniasis, most lethal form of Leishmaniasis, is caused by Leishmania infantum in the Old world. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug resistant strains. Thiol-redox metabolism involving trypanothione and trypanothione reductase, key for survival of Leishmania, is a validated target for rational drug design. Recently published structure of trypanothione reductase (TryR) from L. infantum, in oxidized and reduced form along with Sb(III), provides vital clues on active site of the enzyme. In continuation with our attempts to identify potent inhibitors of TryR, we have modeled binding modes of selected tricyclic compounds and quinone derivatives, using AutoDock4. Here, we report a unique binding mode for quinone derivatives and 9-aminoacridine derivatives, at the FAD binding domain. A conserved hydrogen bonding pattern was observed in all these compounds with residues Thr335, Lys60, His461. With the fact that these residues aid in the orientation of FAD towards the active site forming the core of the FAD binding domain, designing selective and potent compounds that could replace FAD in vivo during the synthesis of Trypanothione reductase can be deployed as an effective strategy in designing new drugs towards Leishmaniasis. We also report the binding of Phenothiazine and 9-aminoacridine derivatives at the Z site of the protein. The biological significance and possible mode of inhibition by quinone derivatives, which binds to FAD binding domain, along with other compounds are discussed.

Journal ArticleDOI
TL;DR: A detailed analysis of the results indicates that the intrinsic solvent effects arise both from solvent‐induced structural changes and from electrostatic solute–solvent interactions, the latter being dominant.
Abstract: Electronic spectra of guanine in the gas phase and in water were studied by quantum mechanical/molecular mechanical (QM/MM) methods. Geometries for the excited-state calculations were extracted from ground-state molecular dynamics (MD) simulations using the self-consistent-charge density functional tight binding (SCC-DFTB) method for the QM region and the TIP3P force field for the water environment. Theoretical absorption spectra were generated from excitation energies and oscillator strengths calculated for 50 to 500 MD snapshots of guanine in the gas phase (QM) and in solution (QM/MM). The excited-state calculations used time-dependent density functional theory (TDDFT) and the DFT-based multireference configuration interaction (DFT/MRCI) method of Grimme and Waletzke, in combination with two basis sets. Our investigation covered keto-N7H and keto-N9H guanine, with particular focus on solvent effects in the low-energy spectrum of the keto-N9H tautomer. When compared with the vertical excitation energies of gas-phase guanine at the optimized DFT (B3LYP/TZVP) geometry, the maxima in the computed solution spectra are shifted by several tenths of an eV. Three effects contribute: the use of SCC-DFTB-based rather than B3LYP-based geometries in the MD snapshots (red shift of ca. 0.1 eV), explicit inclusion of nuclear motion through the MD snapshots (red shift of ca. 0.1 eV), and intrinsic solvent effects (differences in the absorption maxima in the computed gas-phase and solution spectra, typically ca. 0.1-0.3 eV). A detailed analysis of the results indicates that the intrinsic solvent effects arise both from solvent-induced structural changes and from electrostatic solute-solvent interactions, the latter being dominant.

Journal ArticleDOI
TL;DR: The electrostatic properties of halogen atoms are studied theoretically in relation to their ability of Halogen bonding, which is an attractive intermolecular interaction of a covalently bonded halogen atom with a negatively charged atom of a neighboring molecule.
Abstract: The electrostatic properties of halogen atoms are studied theoretically in relation to their ability of halogen bonding, which is an attractive intermolecular interaction of a covalently bonded halogen atom with a negatively charged atom of a neighboring molecule The electric quadrupole (of electronic origin) with a positive zz component Θzz of a covalently bonded halogen atom, where the z axis is taken along the covalent bond involving the halogen atom, is mainly responsible for the attractive electrostatic interaction with a negatively charged atom This positive Θzz is an intrinsic property of halogen atoms with the px2py2pz configuration of the valence electronic shell, as shown by ab initio molecular orbital calculations for isolated halogen atoms with this electronic configuration, and increases in the order of F < Cl < Br < I, in parallel with the known general sequence of the strength of halogen bonding For halogen-containing aromatic compounds, the substituent effects on the electrostatic properties are also studied It is shown that the magnitude of Θzz and the electric field originating from it are rather insensitive to the substituent effect, whereas the electric field originating from atomic partial charges has a large substituent effect The latter electric field tends to partially cancel the former The extent of this partial cancellation is reduced in the order of Cl < Br < I and is also reducible by proper substitution on or within the six-membered ring of halobenzene Perspectives on the development of potential function parameters applicable to halogen-bonding systems are also briefly discussed © 2009 Wiley Periodicals, Inc J Comput Chem 2010

Journal ArticleDOI
TL;DR: A dataset of protein‐drug complexes with experimental binding energy and crystal structure was analyzed and the performance of different docking engines and scoring functions for predicting the free energy of binding and several ligand efficiency indices were compared.
Abstract: A dataset of protein-drug complexes with experimental binding energy and crystal structure were analyzed and the performance of different docking engines and scoring functions (as well as components of these) for predicting the free energy of binding and several ligand efficiency indices were compared. The aim was not to evaluate the best docking method, but to determine the effect of different efficiency indices on the experimental and predicted free energy. Some ligand efficiency indices, such as DeltaG/W (Wiener index), DeltaG/NoC (number of carbons), and DeltaG/P (partition coefficient), improve the correlation between experimental and calculated values. This effect was shown to be valid across the different scoring functions and docking programs. It also removes the common bias of scoring functions in favor of larger ligands. For all scoring functions, the efficiency indices effectively normalize the free energy derived indices, to give values closer to experiment. Compound collection filtering can be done prior or after docking, using pharmacokinetic as well as pharmacodynamic profiles. Achieving these better correlations with experiment can improve the ability of docking scoring functions to predict active molecules in virtual screening.

Journal ArticleDOI
TL;DR: This toolkit is designed to assist in the different stages of an ONIOM QM/MM study of biomolecules, including input file preparation and checking, job monitoring, production calculations, and results analysis.
Abstract: A general procedure for quantum mechanics and molecular mechanics (QM/MM) studies on biochemical systems is outlined, and a collection of PERL scripts to facilitate ONIOM-type QM/MM calculations is described. This toolkit is designed to assist in the different stages of an ONIOM QM/MM study of biomolecules, including input file preparation and checking, job monitoring, production calculations, and results analysis. An iterative procedure for refitting the partial charges of QM region atoms is described and yields a more accurate treatment of the electrostatic interaction between QM and MM regions during QM/MM calculations. The toolkit fully supports this partial charge-refitting procedure. By using this toolkit for file conversions, structure manipulation, input sanity checks, parameter lookup, charge refitting, tracking optimizations, and analyzing results, QM/MM studies of large size biochemical systems can be much more convenient and practical.

Journal ArticleDOI
TL;DR: It is found that inclusion of the quadrupoles moment significantly improves the interaction potential and the inclusion of higher‐order polarizabilities up to quadrupole–quadrupole polarizability is shown to give a better description of the intermolecular interaction.
Abstract: To increase the accuracy of molecular force fields a systematical and balanced improvement of the various terms included is needed. In this work, we have followed this strategy to improve the quality of the NEMO potential for the formaldehyde dimer by introducing local quadrupole moments and higher-order polarizabilities. It is found that inclusion of the quadrupole moment significantly improves the interaction potential. Furthermore, the inclusion of higher-order polarizabilities up to quadrupole-quadrupole polarizability is shown to give a better description of the intermolecular interaction. In addition, it is demonstrated that localized properties based on MP2 densities reproduces the BSSE corrected MP2 interaction energy at large intermolecular separations. This is not the case for HF-SCF based properties.

Journal ArticleDOI
TL;DR: The ForceFit program package is an easy‐to‐use, nonproprietary platform that enables gradient fitting of a wide variety of functional force field forms to quantum mechanical information obtained from an array of common electronic structure codes.
Abstract: The ForceFit program package has been developed for fitting classical force field parameters based upon a force matching algorithm to quantum mechanical gradients of configurations that span the potential energy surface of the system. The program, which runs under UNIX and is written in C++, is an easy-to-use, nonproprietary platform that enables gradient fitting of a wide variety of functional force field forms to quantum mechanical information obtained from an array of common electronic structure codes. All aspects of the fitting process are run from a graphical user interface, from the parsing of quantum mechanical data, assembling of a potential energy surface database, setting the force field, and variables to be optimized, choosing a molecular mechanics code for comparison to the reference data, and finally, the initiation of a least squares minimization algorithm. Furthermore, the code is based on a modular templated code design that enables the facile addition of new functionality to the program.

Journal ArticleDOI
TL;DR: A novel multiple ligand simultaneous docking (MLSD) strategy is proposed, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring and compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems.
Abstract: Present docking methodologies simulate only one single ligand at a time during docking process. In reality, the molecular recognition process always involves multiple molecular species. Typical protein-ligand interactions are, for example, substrate and cofactor in catalytic cycle; metal ion coordination together with ligand(s); and ligand binding with water molecules. To simulate the real molecular binding processes, we propose a novel multiple ligand simultaneous docking (MLSD) strategy, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring. The work also compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems. The methodology proves robust through systematic testing against several diverse model systems: E. coli purine nucleoside phosphorylase (PNP) complex with two substrates, SHP2NSH2 complex with two peptides and Bcl-xL complex with ABT-737 fragments. In all cases, the final correct docking poses and relative binding free energies were obtained. In PNP case, the simulations also capture the binding intermediates and reveal the binding dynamics during the recognition processes, which are consistent with the proposed enzymatic mechanism. In the other two cases, conventional single-ligand docking fails due to energetic and dynamic coupling among ligands, whereas MLSD results in the correct binding modes. These three cases also represent potential applications in the areas of exploring enzymatic mechanism, interpreting noisy X-ray crystallographic maps, and aiding fragment-based drug design, respectively.

Journal ArticleDOI
Jingheng Wu1, Juan Mei1, Sixiang Wen1, Si-Yan Liao1, Jin-Can Chen1, Yong Shen1 
TL;DR: The introduced methods for validation, including leave‐multiple‐out, Y‐randomization, and external validation, proved the superiority of the established GA‐ANN models over MLR models in both stability and predictive power.
Abstract: Based on the quantitative structure-activity relationships (QSARs) models developed by artificial neural networks (ANNs), genetic algorithm (GA) was used in the variable-selection approach with molecule descriptors and helped to improve the back-propagation training algorithm as well. The cross validation techniques of leave-one-out investigated the validity of the generated ANN model and preferable variable combinations derived in the GAs. A self-adaptive GA-ANN model was successfully established by using a new estimate function for avoiding over-fitting phenomenon in ANN training. Compared with the variables selected in two recent QSAR studies that were based on stepwise multiple linear regression (MLR) models, the variables selected in self-adaptive GA-ANN model are superior in constructing ANN model, as they revealed a higher cross validation (CV) coefficient (Q2) and a lower root mean square deviation both in the established model and biological activity prediction. The introduced methods for validation, including leave-multiple-out, Y-randomization, and external validation, proved the superiority of the established GA-ANN models over MLR models in both stability and predictive power. Self-adaptive GA-ANN showed us a prospect of improving QSAR model. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010

Journal ArticleDOI
TL;DR: The proposed method, N‐Ace, is evaluated using independent test sets in various acetylated residues and predictive accuracies of 90% were achieved, indicating that the performance of N-Ace is comparable with that of other acetylation prediction methods.
Abstract: Protein acetylation, which is catalyzed by acetyltransferases, is a type of post-translational modification and crucial to numerous essential biological processes, including transcriptional regulation, apoptosis, and cytokine signaling. As the experimental identification of protein acetylation sites is time consuming and laboratory intensive, several computational approaches have been developed for identifying the candidates of experimental validation. In this work, solvent accessibility and the physicochemical properties of proteins are utilized to identify acetylated alanine, glycine, lysine, methionine, serine, and threonine. A two-stage support vector machine was applied to learn the computational models with combinations of amino acid sequences, and the accessible surface area and physicochemical properties of proteins. The predictive accuracy thus achieved is 5% to 14% higher than that of models trained using only amino acid sequences. Additionally, the substrate specificity of the acetylated site was investigated in detail with reference to the subcellular colocalization of acetyltransferases and acetylated proteins. The proposed method, N-Ace, is evaluated using independent test sets in various acetylated residues and predictive accuracies of 90% were achieved, indicating that the performance of N-Ace is comparable with that of other acetylation prediction methods. N-Ace not only provides a user-friendly input/output interface but also is a creative method for predicting protein acetylation sites. This novel analytical resource is now freely available at http://N-Ace.mbc.NCTU.edu.tw/.

Journal ArticleDOI
Yin-Feng Wang1, Zhi-Ru Li1, Di Wu1, Chia-Chung Sun1, Feng Long Gu2 
TL;DR: It is proven, by examining the singly occupied molecular orbital (SOMO) and the spin density map of e−@C60F 60, that the excess electron is indeed encapsulated inside the C60F60 cage.
Abstract: A new kind of solvated electron systems, sphere-shaped e(-)@C60F60 (I(h)) and capsule-shaped e(-)@C60F60 (D6h), in contrast to the endohedral complex M@C60, is represented at the B3LYP/6-31G(d) + dBF (diffusive basis functions) density functional theory. It is proven, by examining the singly occupied molecular orbital (SOMO) and the spin density map of e(-)@C60F60, that the excess electron is indeed encapsulated inside the C60F60 cage. The shape of the electron cloud in SOMO matches with the shape of C60F60 cage. These cage-like single molecular solvated electrons have considerably large vertical electron detachment energies VDE of 4.95 (I(h)) and 4.67 eV (D6h) at B3LYP/6-31+G(3df) + dBF level compared to the VDE of 3.2 eV for an electron in bulk water (Coe et al., Int Rev Phys Chem 2001, 20, 33) and that of 3.66 eV for e(-)@C20F20 (Irikura, J Phys Chem A 2008, 112, 983), which shows their higher stability. The VDE of the sphere-shaped e(-)@C60F60 (I(h)) is greater than that of the capsule-shaped e(-)@C60F60 (D6h), indicating that the excess electron prefers to reside in the cage with the higher symmetry to form the more stable solvated electron. It is also noticed that the cage size [7.994 (I(h)), 5.714 and 9.978 A (D6h) in diameter] is much larger than that (2.826 A) of (H2O)20- dodecahedral cluster (Khan, Chem Phys Lett 2005, 401, 85).

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TL;DR: In this paper, the authors developed a polarizable force field for biological molecules, which can be used to simulate a range of gas and condensed phase properties, including methanethiol, ethanethiol and methionine residues in proteins.
Abstract: Condensed-phase computational studies of molecules using molecular mechanics approaches require the use of force fields to describe the energetics of the systems as a function of structure. The advantage of polarizable force fields over nonpolarizable (or additive) models lies in their ability to vary their electronic distribution as a function of the environment. Toward development of a polarizable force field for biological molecules, parameters for a series of sulfur-containing molecules are presented. Parameter optimization was performed to reproduce quantum mechanical and experimental data for gas phase properties including geometries, conformational energies, vibrational spectra, and dipole moments as well as for condensed phase properties such as heats of vaporization, molecular volumes, and free energies of hydration. Compounds in the training set include methanethiol, ethanethiol, propanethiol, ethyl methyl sulfide, and dimethyl disulfide. The molecular volumes and heats of vaporization are in good accordance with experimental values, with the polarizable model performing better than the CHARMM22 nonpolarizable force field. Improvements with the polarizable model were also obtained for molecular dipole moments and in the treatment of intermolecular interactions as a function of orientation, in part due to the presence of lone pairs and anisotropic atomic polarizability on the sulfur atoms. Significant advantage of the polarizable model was reflected in calculation of the dielectric constants, a property that CHARMM22 systematically underestimates. The ability of this polarizable model to accurately describe a range of gas and condensed phase properties paves the way for more accurate simulation studies of sulfur-containing molecules including cysteine and methionine residues in proteins.

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TL;DR: The B2PLYP‐D/6-311++G(d,p)//SMD M06‐2X/6‐31+G( d) level of theory provides the populations of backbone and/or prolyl peptide bond for the alanine and proline dipeptides in water that are consistent with the observed values.
Abstract: Density functionals with long-range and/or empirical dispersion corrections, including LC-ωPBE, B97-D, ωB97X-D, M06-2X, B2PLYP-D, and mPW2PLYP-D functionals, are assessed for their ability to describe the conformational preferences of Ac-Ala-NHMe (the alanine dipeptide) and Ac-Pro-NHMe (the proline dipeptide) in the gas phase and in water, which have been used as prototypes for amino acid residues of peptides. For both dipeptides, the mean absolute deviation (MAD) is estimated to be 0.22-0.40 kcal/mol in conformational energy and 2.0-3.2° in torsion angles φ and ψ using these functionals with the 6-311++G(d,p) basis set against the reference values calculated at the MP2/aug-cc-pVTZ//MP2/aug-cc-pVDZ level of theory in the gas phase. The overall performance is obtained in the order B2PLYP-D ≈ mPW2PLYP-D > ωB97X-D ≈ M06-2X > MP2 > LC-ωPBE > B3LYP with the 6-311++G(d,p) basis set. The SMD model at the M06-2X/6-31+G(d) level of theory well reproduced experimental hydration free energies of the model compounds for backbone and side chains of peptides with MADs of 0.47 and 4.3 kcal/mol for 20 neutral and 5 charged molecules, respectively. The B2PLYP-D/6-311++G(d,p)//SMD M06-2X/6-31+G(d) level of theory provides the populations of backbone and/or prolyl peptide bond for the alanine and proline dipeptides in water that are consistent with the observed values.