New protein parameters are reported for the all-atom empirical energy function in the CHARMM program. The parameter evaluation was based on a self-consistent approach designed to achieve a balance between the internal (bonding) and interaction (nonbonding) terms of the force field and among the solvent−solvent, solvent−solute, and solute−solute interactions. Optimization of the internal parameters used experimental gas-phase geometries, vibrational spectra, and torsional energy surfaces supplemented with ab initio results. The peptide backbone bonding parameters were optimized with respect to data for N-methylacetamide and the alanine dipeptide. The interaction parameters, particularly the atomic charges, were determined by fitting ab initio interaction energies and geometries of complexes between water and model compounds that represented the backbone and the various side chains. In addition, dipole moments, experimental heats and free energies of vaporization, solvation and sublimation, molecular volume...

/pdf/all-atom-empirical-potential-for-molecular-modeling-and-2nds0dxw12.pdf

All-atom empirical potential for molecular modeling and dynamics studies of proteins.

This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.

/pdf/gromacs-fast-flexible-and-free-15aazpel5u.pdf

GROMACS: Fast, flexible, and free

The ff94 force field that is commonly associated with the Amber simulation package is one of the most widely used parameter sets for biomolecular simulation. After a decade of extensive use and testing, limitations in this force field, such as over-stabilization of alpha-helices, were reported by us and other researchers. This led to a number of attempts to improve these parameters, resulting in a variety of "Amber" force fields and significant difficulty in determining which should be used for a particular application. We show that several of these continue to suffer from inadequate balance between different secondary structure elements. In addition, the approach used in most of these studies neglected to account for the existence in Amber of two sets of backbone phi/psi dihedral terms. This led to parameter sets that provide unreasonable conformational preferences for glycine. We report here an effort to improve the phi/psi dihedral terms in the ff99 energy function. Dihedral term parameters are based on fitting the energies of multiple conformations of glycine and alanine tetrapeptides from high level ab initio quantum mechanical calculations. The new parameters for backbone dihedrals replace those in the existing ff99 force field. This parameter set, which we denote ff99SB, achieves a better balance of secondary structure elements as judged by improved distribution of backbone dihedrals for glycine and alanine with respect to PDB survey data. It also accomplishes improved agreement with published experimental data for conformational preferences of short alanine peptides and better accord with experimental NMR relaxation data of test protein systems.

/pdf/comparison-of-multiple-amber-force-fields-and-development-of-2mpeu0hj18.pdf

Comparison of multiple Amber force fields and development of improved protein backbone parameters.

Recent advances in hardware and software have enabled increasingly long molecular dynamics (MD) simulations of biomolecules, exposing certain limitations in the accuracy of the force fields used for such simulations and spurring efforts to refine these force fields. Recent modifications to the Amber and CHARMM protein force fields, for example, have improved the backbone torsion potentials, remedying deficiencies in earlier versions. Here, we further advance simulation accuracy by improving the amino acid side-chain torsion potentials of the Amber ff99SB force field. First, we used simulations of model alpha-helical systems to identify the four residue types whose rotamer distribution differed the most from expectations based on Protein Data Bank statistics. Second, we optimized the side-chain torsion potentials of these residues to match new, high-level quantum-mechanical calculations. Finally, we used microsecond-timescale MD simulations in explicit solvent to validate the resulting force field against a large set of experimental NMR measurements that directly probe side-chain conformations. The new force field, which we have termed Amber ff99SB-ILDN, exhibits considerably better agreement with the NMR data. Proteins 2010. © 2010 Wiley-Liss, Inc.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/prot.22711

Improved side‐chain torsion potentials for the Amber ff99SB protein force field

The widely used CHARMM additive all-atom force field includes parameters for proteins, nucleic acids, lipids, and carbohydrates. In the present article, an extension of the CHARMM force field to drug-like molecules is presented. The resulting CHARMM General Force Field (CGenFF) covers a wide range of chemical groups present in biomolecules and drug-like molecules, including a large number of heterocyclic scaffolds. The parametrization philosophy behind the force field focuses on quality at the expense of transferability, with the implementation concentrating on an extensible force field. Statistics related to the quality of the parametrization with a focus on experimental validation are presented. Additionally, the parametrization procedure, described fully in the present article in the context of the model systems, pyrrolidine, and 3-phenoxymethylpyrrolidine will allow users to readily extend the force field to chemical groups that are not explicitly covered in the force field as well as add functional groups to and link together molecules already available in the force field. CGenFF thus makes it possible to perform "all-CHARMM" simulations on drug-target interactions thereby extending the utility of CHARMM force fields to medicinally relevant systems.

/pdf/charmm-general-force-field-a-force-field-for-drug-like-4mhn8ejv47.pdf

CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields.

We present results of improving the OPLS-AA force field for peptides by means of refitting the key Fourier torsional coefficients. The fitting technique combines using accurate ab initio data as the target, choosing an efficient fitting subspace of the whole potential-energy surface, and determining weights for each of the fitting points based on magnitudes of the potential-energy gradient. The average energy RMS deviation from the LMP2/cc-pVTZ(-f)//HF/6-31G** data is reduced by ca. 40% from 0.81 to 0.47 kcal/mol as a result of the fitting for the electrostatically uncharged dipeptides. Transferability of the parameters is demonstrated by using the same alanine dipeptide-fitted backbone torsional parameters for all of the other dipeptides (with the appropriate side-chain refitting) and the alanine tetrapeptide. Parameters of nonbonded interactions have also been refitted for the sulfur-containing dipeptides (cysteine and methionine), and the validity of the new Coulombic charges and the van der Waals σ's ...

/pdf/evaluation-and-reparametrization-of-the-opls-aa-force-field-1eolo8h5re.pdf

Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides†

Current “second-generation” force fields have been developed for use in Monte Carlo and molecular dynamics simulations for organic and biomolecular systems in solution. The performance of three such force fields, AMBER94, MMFF94, and OPLS-AA, is tested here through Monte Carlo (MC) statistical mechanics simulations for liquid butane, methanol, and N-methylacetamide (NMA). These liquids were chosen for their range of polarity and their representation of typical interactions found in proteins. From simulations at constant temperature and 1 atm pressure, the average errors in the computed densities and heats of vaporization are 3.8% and 5.1% with AMBER94 and 1.5% and 1.3% with OPLS-AA. With MMFF94, the computed densities and heats of vaporization for methanol and NMA are too low by 21−27%, while butane at −0.5 °C does not stop expanding during the simulation. A MC simulation using MMFF94 for butane with the density fixed at the experimental value yields a 32% error in the energy of vaporization. Analyses sho...

Performance of the amber94, mmff94, and opls-aa force fields for modeling organic liquids

A combined quantum mechanical and molecular mechanical method is presented and tested through Monte Carlo statistical mechanics simulations. The method is general and computationally efficient for obtaining energetic and structural results for organic processes in the liquid phase. The solutes are represented quantum mechanically through AM1 calculations, and the solvent is treated explicitly with classical OPLS potential functions. The interaction between the quantum and classical parts of the systems is computed classically using scaled partial charges for the solute atoms that are derived from the AM1 wave function via the CM1A procedure of Cramer and Truhlar. The new methodology is tested through computation of free energies of hydration of thirteen diverse organic molecules, the medium dependence of the conformational equilibria for 1,2-dichloroethane and furfural, the acceleration of the Claisen rearrangement of allyl vinyl ether in water, and the medium dependence of the tautomeric equilibrium for ...

George A. Kaminski and

Papers

Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides†

Performance of the amber94, mmff94, and opls-aa force fields for modeling organic liquids

A Quantum Mechanical and Molecular Mechanical Method Based on CM1A Charges: Applications to Solvent Effects on Organic Equilibria and Reactions