Showing papers by "Adrian E. Roitberg published in 2012"

MMPBSA.py: An Efficient Program for End-State Free Energy Calculations.

Abstract: MM-PBSA is a post-processing end-state method to calculate free energies of molecules in solution. MMPBSA.py is a program written in Python for streamlining end-state free energy calculations using ensembles derived from molecular dynamics (MD) or Monte Carlo (MC) simulations. Several implicit solvation models are available with MMPBSA.py, including the Poisson–Boltzmann Model, the Generalized Born Model, and the Reference Interaction Site Model. Vibrational frequencies may be calculated using normal mode or quasi-harmonic analysis to approximate the solute entropy. Specific interactions can also be dissected using free energy decomposition or alanine scanning. A parallel implementation significantly speeds up the calculation by dividing frames evenly across available processors. MMPBSA.py is an efficient, user-friendly program with the flexibility to accommodate the needs of users performing end-state free energy calculations. The source code can be downloaded at http://ambermd.org/ with AmberTools, rele...

Identification of unavoided crossings in nonadiabatic photoexcited dynamics involving multiple electronic states in polyatomic conjugated molecules

Abstract: Radiationless transitions between electronic excited states in polyatomic molecules take place through unavoided crossings of the potential energysurfaces with substantial non-adiabatic coupling between the respective adiabatic states. While the extent in time of these couplings are large enough, these transitions can be reasonably well simulated through quantum transitions using trajectory surface hopping-like methods. In addition, complex molecular systems may have multiple “trivial” unavoided crossings between noninteracting states. In these cases, the non-adiabatic couplings are described as sharp peaks strongly localized in time. Therefore, their modeling is commonly subjected to the identification of regions close to the particular instantaneous nuclear configurations for which the energysurfaces actually cross each other. Here, we present a novel procedure to identify and treat these regions of unavoided crossings between non-interacting states using the so-called Min-Cost algorithm. The method differentiates between unavoided crossings between interacting states (simulated by quantum hops), and trivial unavoided crossings between non-interacting states (detected by tracking the states in time with Min-Cost procedure). We discuss its implementation within our recently developed non-adiabaticexcited statemolecular dynamics framework. Fragments of two- and four-ring linear polyphenylene ethynylene chromophore units at various separations have been used as a representative molecular system to test the algorithm. Our results enable us to distinguish and analyze the main features of these different types of radiationless transitions the molecular system undertakes during internal conversion.

pH-Dependent Conformational Changes in Proteins and Their Effect on Experimental pKas: The Case of Nitrophorin 4

Abstract: The acid-base behavior of amino acids is an important subject of study due to their prominent role in enzyme catalysis, substrate binding and protein structure. Due to interactions with the protein environment, their pKas can be shifted from their solution values and, if a protein has two stable conformations, it is possible for a residue to have different “microscopic”, conformation-dependent pKa values. In those cases, interpretation of experimental measurements of the pKa is complicated by the coupling between pH, protonation state and protein conformation. We explored these issues using Nitrophorin 4 (NP4), a protein that releases NO in a pH sensitive manner. At pH 5.5 NP4 is in a closed conformation where NO is tightly bound, while at pH 7.5 Asp30 becomes deprotonated, causing the conformation to change to an open state from which NO can easily escape. Using constant pH molecular dynamics we found two distinct microscopic Asp30 pKas: 8.5 in the closed structure and 4.3 in the open structure. Using a four-state model, we then related the obtained microscopic values to the experimentally observed “apparent” pKa, obtaining a value of 6.5, in excellent agreement with experimental data. This value must be interpreted as the pH at which the closed to open population transition takes place. More generally, our results show that it is possible to relate microscopic structure dependent pKa values to experimentally observed ensemble dependent apparent pKas and that the insight gained in the relatively simple case of NP4 can be useful in several more complex cases involving a pH dependent transition, of great biochemical interest.

Enhancing Conformation and Protonation State Sampling of Hen Egg White Lysozyme Using pH Replica Exchange Molecular Dynamics.

Abstract: We evaluate the efficiency of the pH replica exchange molecular dynamics (pH-REMD) method proposed by Itoh et al. (Proteins2011, 79, 3420–3436) by using it to predict the pKa values of the titratable residues in hen egg white lysozyme (HEWL). pKa values predicted using pH-REMD converge significantly faster than those calculated using constant pH molecular dynamics (CpHMD). Furthermore, increasing the frequency between exchange attempts in pH-REMD simulations improves protonation and conformational state sampling. By enabling the simulation to sample both conformational and protonation states more rapidly, pH-REMD simulations provide valuable insight into the pH-dependence of HEWL that the CpHMD simulations failed to capture. We present an efficient and highly scalable implementation of pH-REMD as an attractive enhancement to traditional CpHMD methods.

Nonadiabatic excited-state molecular dynamics: numerical tests of convergence and parameters.

Abstract: Nonadiabatic molecular dynamics simulations, involving multiple Born-Oppenheimer potential energy surfaces, often require a large number of independent trajectories in order to achieve the desired convergence of the results, and simulation relies on different parameters that should be tested and compared. In addition to influencing the speed of the simulation, the chosen parameters combined with the frequently reduced number of trajectories can sometimes lead to unanticipated changes in the accuracy of the simulated dynamics. We have previously developed a nonadiabatic excited state molecular dynamics methodology employing Tully's fewest switches surface hopping algorithm. In this study, we seek to investigate the impact of the number of trajectories and the various parameters on the simulation of the photoinduced dynamics of distyrylbenzene (a small oligomer of polyphenylene vinylene) within our developed framework. Various user-defined parameters are analyzed: classical and quantum integration time steps, the value of the friction coefficient for Langevin dynamics, and the initial seed used for stochastic thermostat and hopping algorithms. Common approximations such as reduced number of nonadiabatic coupling terms and the classical path approximation are also investigated. Our analysis shows that, at least for the considered molecular system, a minimum of ~400 independent trajectories should be calculated in order to achieve statistical averaging necessary for convergence of the calculated relaxation timescales.

Shishiodoshi unidirectional energy transfer mechanism in phenylene ethynylene dendrimers.

Abstract: Non-adiabatic excited-state molecular dynamics is used to study the ultrafast intramolecular energy transfer between two-, three-, and four-ring linear polyphenylene ethynylene chromophore units linked through meta-substitutions. Twenty excited-state electronic energies, with their corresponding gradients and nonadiabatic coupling vectors were included in the simulations. The initial laser excitation creates an exciton delocalized between the different absorbing two-ring linear PPE units. Thereafter, we observe an ultrafast directional change in the spatial localization of the transient electronic transition density. The analysis of the intramolecular flux of the transition density shows a sequential through-bond two-ring→three-ring→four-ring transfer as well as an effective through-space direct two-to-four ring transfer. The vibrational excitations of C≡C stretching motions change according to that. Finally, a mechanism of unidirectional energy transfer is presented based on the variation of the energy gaps between consecutive electronic excited states in response to the intramolecular flux of the transition density. The mechanism resembles a Shishiodoshi Japanese bamboo water fountain where, once the electronic population has been transferred to the state directly below in energy, the two states decouple thereby preventing energy transfer in the opposite direction.

Analysis of state-specific vibrations coupled to the unidirectional energy transfer in conjugated dendrimers.

Abstract: The nonadiabatic excited-state molecular dynamics (NA-ESMD) method and excited-state instantaneous normal modes (ES-INMs) analyses have been applied to describe the state-specific vibrations that participate in the unidirectional energy transfer between the coupled chromophores in a branched dendrimeric molecule. Our molecule is composed of two-, three-, and four-ring linear poly(phenyleneethynylene) (PPE) units linked through meta-substitutions. After an initial laser excitation, an ultrafast sequential S3 → S2 → S1 electronic energy transfer from the shortest to longest segment takes place. During each Sn → Sn–1 (n = 3, 2) transition, ES-INM(Sn) and ES-INM(Sn–1) analyses have been performed on Sn and Sn–1 states, respectively. Our results reveal a unique vibrational mode localized on the Sn state that significantly matches with the corresponding nonadiabatic coupling vector dn,(n–1). This mode also corresponds to the highest frequency ES-INM(Sn) and it is seen mainly during the electronic transitions. F...

Wide-Open Flaps are Key to Urease Activity

Abstract: Substrate ingress and product egress from the active site of urease is tightly controlled by an active-site flap. Molecular dynamics simulations of urease have revealed a previously unobserved wide-open flap state that, unlike the well-characterized closed and open states, allows ready access to the metal cluster in the active site. This state is easily reached from the open state via low free energy barriers. Additionally, we have found that even when the flap is closed, a region of the binding pocket is solvent-exposed, leading to the hypothesis that it may act as a substrate/product reservoir. The newly identified wide-open state offers further opportunities for small-molecule drug discovery by defining a more extensive active-site pocket than has been previously described.

pH-Replica Exchange Molecular Dynamics In Proteins Using A Discrete Protonation Method

Abstract: Protonation equilibria in biological molecules modulates structure, dynamics, and function. A pH-replica exchange molecular dynamics (pH-REMD) method is described here to improve the coupling between conformational and protonation sampling. Under a Hamiltonian replica exchange setup, conformations are swapped between two neighboring replicas, which themselves are at different pHs. The method has been validated on a series of biological systems. We applied pH-REMD to a series of model compounds, to an terminally charged ADFDA pentapeptide, and to a heptapeptide derived from the ovomucoid third domain (OMTKY3). In all of those systems, the predicted pKa by pH-REMD is very close to the experimental value and almost identical to the ones obtained by constant pH molecular dynamics (CpH MD). The method presented here, pH-REMD, has the advantage of faster convergence properties due to enhanced sampling of both conformation and protonation spaces.

pH-Replica Exchange Molecular Dynamics in Proteins Using a Discrete Protonation Method

Abstract: Protonation equilibria in biological molecules modulates structure, dynamics, and function. A pH-replica exchange molecular dynamics (pH-REMD) method is described here to improve the coupling between conformational and protonation sampling. Under a Hamiltonian replica exchange setup, conformations are swapped between two neighboring replicas, which themselves are at different pHs. The method has been validated on a series of biological systems. We applied pH-REMD to a series of model compounds, to an terminally charged ADFDA pentapeptide, and to a heptapeptide derived from the ovomucoid third domain (OMTKY3). In all of those systems, the predicted pKₐ by pH-REMD is very close to the experimental value and almost identical to the ones obtained by constant pH molecular dynamics (CpH MD). The method presented here, pH-REMD, has the advantage of faster convergence properties due to enhanced sampling of both conformation and protonation spaces.

Conjugated Polyelectrolyte Dendrimers: Aggregation, Photophysics, and Amplified Quenching

Abstract: Conjugated polyelectrolyte dendrimers (CPDs) are monodisperse macromolecules that feature a fully π-conjugated dendrimer core surrounded on the periphery by ionic solubilizing groups. CPDs are soluble in water and polar organic solvents, and they exhibit photophysics characteristic of the π-conjugated chromophores comprising the dendrimer core. Here we describe the synthesis and photophysical characterization of series of three generations of CPDs based on a phenylene ethynylene repeat unit structure that is surrounded by an array of anionic sodium carboxylate groups. Molecular dynamics simulations indicate that the first-generation CPD is flat while the second- and third-generation CPDs adopt oblate structures. Photophysical studies, including absorption, fluorescence spectroscopy, and lifetimes, show that the ester protected precursor dendrimers exhibit highly efficient blue fluorescence in THF solution emanating from the phenylene ethynylene chromophore that is in the dendrimer core. By contrast, the w...

Enzyme dynamics and catalysis in the mechanism of DNA polymerase

Abstract: This contribution contains the commentaries of the three authors about two papers in this issue of TCA that present alternative views of the role of conformational changes in the specificity of enzyme DNA polymerase β. Concepts such as dynamical effects, the induced fit model or the importance of sampling in modeling of enzymatic reactions are briefly revised within the context of the debate established in the two previous papers.

Comment on “a minimal implementation of the AMBER–GAUSSIAN interface for Ab Initio QM/MM‐MD simulation”

Abstract: We comment upon the recent critique of use of the Program for User Package Interfacing and Linking (PUPIL) system for linking AMBER and GAUSSIAN in a multiscale quantum mechanical/molecular mechanics (QM/MM) simulation (Okamoto et al., J. Comput. Chem. 2011, 32, 932). Specifically, their method for computing forces on the MM particles from the QM region via the GAUSSIAN-03 electrical field was already implemented in PUPIL version 1.3, publicly available beginning December 2009. Some other doubtful characterizations of PUPIL are discussed briefly in the context of current awareness of open-source codes more generally. © 2012 Wiley Periodicals, Inc.