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

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. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

The SAAP force field: Development of the single amino acid potentials for 20 proteinogenic amino acids and Monte Carlo molecular simulation for short peptides

Molecular simulation by using force field parameters has been widely applied in the fields of peptide and protein research for various purposes. We recently proposed a new all‐atom protein force field, called the SAAP force field, which utilizes single amino acid potentials (SAAPs) as the fundamental elements. In this article, whole sets of the SAAP force field parameters in vacuo, in ether, and in water have been developed by ab initio calculation for all 20 proteinogenic amino acids and applied to Monte Carlo molecular simulation for two short peptides. The side‐chain separation approximation method was employed to obtain the SAAP parameters for the amino acids with a long side chain. Monte Carlo simulation for Met‐enkephalin (CHO‐Tyr‐Gly‐Gly‐Phe‐Met‐NH₂) by using the SAAP force field revealed that the conformation in vacuo is mainly controlled by strong electrostatic interactions between the amino acid residues, while the SAAPs and the interamino acid Lennard‐Jones potentials are predominant in water. In ether, the conformation would be determined by the combination of the three components. On the other hand, the SAAP simulation for chignolin (H‐Gly‐Tyr‐Asp‐Pro‐Glu‐Thr‐Gly‐Thr‐Trp‐Gly‐OH) reasonably reproduced a native‐like β‐hairpin structure in water although the C‐terminal and side‐chain conformations were different from the native ones. It was suggested that the SAAP force field is a useful tool for analyzing conformations of polypeptides in terms of intrinsic conformational propensities of the single amino acid units. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations

Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report the development of a third-generation point-charge all-atom force field for proteins. Following the earlier approach of Cornell et al., the charge set was obtained by fitting to the electrostatic potentials of dipeptides calculated using B3LYP/cc-pVTZ//HF/6-31G** quantum mechanical methods. The main-chain torsion parameters were obtained by fitting to the energy profiles of Ace-Ala-Nme and Ace-Gly-Nme di-peptides calculated using MP2/cc-pVTZ//HF/6-31G** quantum mechanical methods. All other parameters were taken from the existing AMBER data base. The major departure from previous force fields is that all quantum mechanical calculations were done in the condensed phase with continuum solvent models and an effective dielectric constant of epsilon = 4. We anticipate that this force field parameter set will address certain critical short comings of previous force fields in condensed-phase simulations of proteins. Initial tests on peptides demonstrated a high-degree of similarity between the calculated and the statistically measured Ramanchandran maps for both Ace-Gly-Nme and Ace-Ala-Nme di-peptides. Some highlights of our results include (1) well-preserved balance between the extended and helical region distributions, and (2) favorable type-II poly-proline helical region in agreement with recent experiments. Backward compatibility between the new and Cornell et al. charge sets, as judged by overall agreement between dipole moments, allows a smooth transition to the new force field in the area of ligand-binding calculations. Test simulations on a large set of proteins are also discussed.     

Computer simulation of trifluoromethane properties with ab initio force field

Intermolecular interaction potentials of the trifluoromethane dimer in 15 orientations have been calculated using the Hartree‐Fock (HF) self‐consistent theory and the second‐order Møller‐Plesset (MP2) perturbation theory. Single point energies at important geometries were also calibrated by the coupled cluster with single and double and perturbative triple excitation [CCSD(T)] calculations. We have employed Pople's medium size basis sets [up to 6‐311++G(3df,3pd)] and Dunning's correlation consistent basis sets (up to aug‐cc‐pVQZ). Basis set limit potential values were obtained through well‐studied extrapolation methods. The calculated MP2 potential data were employed to parameterize a 5‐site force field for molecular simulations. We performed molecular dynamics simulations using the constructed ab initio force field and compared the simulation results with experiments. Quantitative agreements for the atom‐wise radial distribution functions and the self‐diffusion coefficients over a wide range of experimental conditions can be obtained, thus validating the ab initio force field without using experimental data a priori. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011     

Conformational simulations of aqueous solvated alpha-conotoxin GI and its single disulfide analogues using a polarizable force field model

The solution conformation of alpha-conotoxin GI and its two single disulfide analogues are simulated using a polarizable force field in combination with the molecular fragmentation quantum chemical calculation. The polarizability is explicitly described by allowing the partial charges and fragment dipole moments to be variables, with values coming from the linear-scaling energy-based molecular fragmentation calculations at the B3LYP/6-31G(d) level. In comparison with the full quantum chemical calculations, the fragmentation approaches can yield precise ground-state energies, dipole moments, and static polarizabilities for peptides. The B3LYP/6-31G(d) charges and fragment-centered dipole moments are introduced in calculations of electrostatic terms in both AmberFF03 and OPLS force fields. Our test calculations on the gas-phase glucagon (PDB code: 1gcn) and solvated alpha-conotoxin GI (PDB code: 1not) demonstrate that the present polarization model is capable of describing the structural properties (such as the relative conformational energies, intramolecular hydrogen bonds, and disulfide bonds) with accuracy comparable to some other polarizable force fields (ABEEM/MM and OPLS-PFF) and the quantum mechanics/molecular mechanics (QM/MM) hybrid model. The employment of fragment-centered dipole moments in calculations of dipole-dipole interactions can save computational time in comparison with those polarization models using atom-centered dipole moments without much loss of accuracy. The molecular dynamics simulations using the polarizable force field demonstrate that two single disulfide GI analogues are more flexible and less structured than the native alpha-conotoxin GI, in agreement with NMR experiments. The polarization effect is important in simulations of the folding/unfolding process of solvated proteins.     

Introduction of periodic boundary conditions into UNRES force field

In this article, implementation of periodic boundary conditions (PBC) into physics‐based coarse‐grained UNited RESidue (UNRES) force field is presented, which replaces droplet‐like restraints previously used. Droplet‐like restraints are necessary to keep multichain systems together and prevent them from dissolving to infinitely low concentration. As an alternative for droplet‐like restrains cuboid PBCs with imaging of the molecules were introduced. Owing to this modification, artificial forces which arose from restraints keeping a droplet together were eliminated what leads to more realistic trajectories. Due to computational reasons cutoff and smoothing functions were introduced on the long range interactions. The UNRES force field with PBC was tested by performing microcanonical simulations. Moreover, to asses the behavior of the thermostat in PBCs Langevin and Berendsen thermostats were studied. The influence of PBCs on association pattern was compared with droplet‐like restraints on the ββα hetero tetramer 1 protein system. © 2015 Wiley Periodicals, Inc.     

Global optimization of parameters in the reactive force field ReaxFF for SiOH

We have used unbiased global optimization to fit a reactive force field to a given set of reference data. Specifically, we have employed genetic algorithms (GA) to fit ReaxFF to SiOH data, using an in‐house GA code that is parallelized across reference data items via the message‐passing interface (MPI). Details of GA tuning turn‐ed out to be far less important for global optimization efficiency than using suitable ranges within which the parameters are varied. To establish these ranges, either prior knowledge can be used or successive stages of GA optimizations, each building upon the best parameter vectors and ranges found in the previous stage. We have finally arrive‐ed at optimized force fields with smaller error measures than those published previously. Hence, this optimization approach will contribute to converting force‐field fitting from a specialist task to an everyday commodity, even for the more difficult case of reactive force fields. © 2013 Wiley Periodicals, Inc.     

Revised CHARMM force field parameters for iron‐containing cofactors of photosystem II

Photosystem II is a complex protein–cofactor machinery that splits water molecules into molecular oxygen, protons, and electrons. All‐atom molecular dynamics simulations have the potential to contribute to our general understanding of how photosystem II works. To perform reliable all‐atom simulations, we need accurate force field parameters for the cofactor molecules. We present here CHARMM bonded and non‐bonded parameters for the iron‐containing cofactors of photosystem II that include a six‐coordinated heme moiety coordinated by two histidine groups, and a non‐heme iron complex coordinated by bicarbonate and four histidines. The force field parameters presented here give water interaction energies and geometries in good agreement with the quantum mechanical target data. © 2017 Wiley Periodicals, Inc.     

Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

The effects of electronic polarization in biomolecular interactions will differ depending on the local dielectric constant of the environment, such as in solvent, DNA, proteins, and membranes. Here the performance of the AMOEBA polarizable force field is evaluated under nonaqueous conditions by calculating the solvation free energies of small molecules in four common organic solvents. Results are compared with experimental data and equivalent simulations performed with the GAFF pairwise‐additive force field. Although AMOEBA results give mean errors close to “chemical accuracy,” GAFF performs surprisingly well, with statistically significantly more accurate results than AMOEBA in some solvents. However, for both models, free energies calculated in chloroform show worst agreement to experiment and individual solutes are consistently poor performers, suggesting non‐potential‐specific errors also contribute to inaccuracy. Scope for the improvement of both potentials remains limited by the lack of high quality experimental data across multiple solvents, particularly those of high dielectric constant. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.     

Using one‐step perturbation to predict the effect of changing force‐field parameters on the simulated folding equilibrium of a β‐peptide in solution

Computer simulation using molecular dynamics is increasingly used to simulate the folding equilibria of peptides and small proteins. Yet, the quality of the obtained results depends largely on the quality of the force field used. This comprises the solute as well as the solvent model and their energetic and entropic compatibility. It is, however, computational very expensive to perform test simulations for each combination of force‐field parameters. Here, we use the one‐step perturbation technique to predict the change of the free enthalpy of folding of a β‐peptide in methanol solution due to changing a variety of force‐field parameters. The results show that changing the solute backbone partial charges affects the folding equilibrium, whereas this is relatively insensitive to changes in the force constants of the torsional energy terms of the force field. Extending the cut‐off distance for nonbonded interactions beyond 1.4 nm does not affect the folding equilibrium. The same result is found for a change of the reaction‐field permittivity for methanol from 17.7 to 30. The results are not sensitive to the criterion, e.g., atom‐positional RMSD or number of hydrogen bonds, that is used to distinguish folded and unfolded conformations. Control simulations with perturbed Hamiltonians followed by backward one‐step perturbation indicated that quite large perturbations still yield reliable results. Yet, perturbing all solvent molecules showed where the limitations of the one‐step perturbation technique are met. The evaluated methodology constitutes an efficient tool in force‐field development for molecular simulation by reducing the number of required separate simulations by orders of magnitude. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Determination of side‐chain‐rotamer and side‐chain and backbone virtual‐bond‐stretching potentials of mean force from AM1 energy surfaces of terminally‐blocked amino‐acid residues,for coarse‐grained simulations of protein structure and folding. I. The method

In this and the accompanying article, we report the development of new physics‐based side‐chain‐rotamer and virtual‐bond‐deformation potentials which now replace the respective statistical potentials used so far in our physics‐based united‐reside UNRES force field for large‐scale simulations of protein structure and dynamics. In this article, we describe the methodology for determining the corresponding potentials of mean force (PMF's) from the energy surfaces of terminally‐blocked amino‐acid residues calculated with the AM1 quantum‐mechanical semiempirical method. The approach is based on minimization of the AM1 energy for fixed values of the angles λ for rotation of the peptide groups about the C^α ··· C^α virtual bonds, and for fixed values of the side‐chain dihedral angles χ, which formed a multidimensional grid. A harmonic‐approximation approach was developed to extrapolate from the energy at a given grid point to other points of the conformational space to compute the respective contributions to the PMF. To test the applicability of the harmonic approximation, the rotamer PMF's of alanine and valine obtained with this approach have been compared with those obtained by using a Metropolis Monte Carlo method. The PMF surfaces computed with the harmonic approximation are more rugged and have more pronounced minima than the MC‐calculated surfaces but the harmonic‐approximation‐and MC‐calculated PMF values are linearly correlated. The potentials derived with the harmonic approximation are, therefore, appropriate for UNRES for which the weights (scaling factors) of the energy terms are determined by force‐field optimization for foldability. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Developing multisite empirical force field models for Pt(II) and cisplatin

We have developed empirical force field parameters for Pt(II) and cisplatin. Two force field frameworks were used—modified OPLS‐AA and our second‐order polarizable POSSIM. A seven‐site model was used for the Pt(II) ion. The goal was to create transferable parameter sets compatible with the force field models for proteins and general organic compounds. A number of properties of the Pt(II) ion and its coordination compounds have been considered, including geometries and energies of the complexes, hydration free energy, and radial distribution functions in water. Comparison has been made with experimental and quantum mechanical results. We have demonstrated that both versions are generally capable of reproducing key properties of the system, but the second‐order polarizable POSSIM formalism permits more accurate quantitative results to be obtained. For example, the energy of formation of cisplatin as calculated with the modified OPLS‐AA exhibited an error of 9.9%, while the POSSIM error for the same quantity was 6.2%. The produced parameter sets are transferable and suitable to be used in protein‐metal binding simulations in which position or even coordination of the ion does not have to be constrained using preexisting knowledge. © 2016 Wiley Periodicals, Inc.     

Parametrization of macrolide antibiotics using the force field toolkit

Macrolides are an important class of antibiotics that target the bacterial ribosome. Computer simulations of macrolides are limited as specific force field parameters have not been previously developed for them. Here, we determine CHARMM‐compatible force field parameters for erythromycin, azithromycin, and telithromycin, using the force field toolkit (ffTK) plugin in VMD. Because of their large size, novel approaches for parametrizing them had to be developed. Two methods for determining partial atomic charges, from interactions with TIP3P water and from the electrostatic potential, as well as several approaches for fitting the dihedral parameters were tested. The performance of the different parameter sets was evaluated by molecular dynamics simulations of the macrolides in ribosome, with a distinct improvement in maintenance of key interactions observed after refinement of the initial parameters. Based on the results of the macrolide tests, recommended procedures for parametrizing very large molecules using ffTK are given. © 2015 Wiley Periodicals, Inc.     

Force field parameters for the simulation of modified histone tails

We describe the development of force field parameters for methylated lysines and arginines, and acetylated lysine for the CHARMM all‐atom force field. We also describe a CHARMM united‐atom force field for modified sidechains suitable for use with fragment‐based docking methods. The development of these parameters is based on results of ab initio quantum mechanics calculations of model compounds with subsequent refinement and validation by molecular mechanics and molecular dynamics simulations. The united‐atom parameters are tested by fragment docking to target proteins using the MCSS procedure. The all‐atom force field is validated by molecular dynamics simulations of multiple experimental structures. In both sets of calculations, the computational predictions using the force field were compared to the corresponding experimental structures. We show that the parameters yield an accurate reproduction of experimental structures. Together with the existing CHARMM force field, these parameters will enable the general modeling of post‐translational modifications of histone tails. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Peptide free‐energy profile is strongly dependent on the force field: Comparison of C96 and AMBER95

The C96 and AMBER95 force fields were compared with small model peptides Ac‐(Ala)_n‐NMe (Ac = CH₃CO, NMe = NHCH₃, n=2 and 3) in vacuo and in TIP3P water by computing the free‐energy profiles using multicanonical molecular dynamics method. The C96 force field is a modified version of the AMBER95 force field, which was adjusted to reproduce the energy difference between extended β‐ and constrained α‐helical energies for the alanine tetrapeptide, obtained by the high level ab initio MO method. The slight modification resulted in a large difference in the free energy profiles. The C96 force field prefers relatively extended conformers, whereas the AMBER95 force field favors turn conformations. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 748–762, 2000     

Beta‐hairpin restraint potentials for calculations of potentials of mean force as a function of beta‐hairpin tilt,rotation, and distance

We have developed a set of restraint potentials for β‐hairpin tilt relative to the membrane normal, β‐hairpin rotation around the β‐hairpin axis, and hairpin–hairpin distance. Such restraint potentials enable us to characterize the molecular basis of specific β‐hairpin tilt and rotation in membranes and hairpin–hairpin interactions at the atomic level by sampling their conformational space along these degrees of freedom, i.e., reaction coordinates, during molecular dynamics simulations. We illustrate the efficacy of the β‐hairpin restraint potentials by calculating the potentials of mean force (PMFs) as a function of tilt and rotation angles of protegrin‐1 (PG‐1), a β‐hairpin antimicrobial peptide, in an implicit membrane model. The peptide association in the membrane is also examined by calculating the PMFs as a function of distance between two PG‐1 peptides in various dimer interfaces. These novel restraint potentials are found to perform well in each of these cases and are expected to be a useful means to study the microscopic driving forces of insertion, tilting, and rotation of β‐hairpin peptides in membranes as well as their association in aqueous solvent or membrane environments particularly when combined with explicit solvent models. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009     

Introduction of steered molecular dynamics into UNRES coarse‐grained simulations package

In this article, an implementation of steered molecular dynamics (SMD) in coarse‐grain UNited RESidue (UNRES) simulations package is presented. Two variants of SMD have been implemented: with a constant force and a constant velocity. The huge advantage of SMD implementation in the UNRES force field is that it allows to pull with the speed significantly lower than the accessible pulling speed in simulations with all‐atom representation of a system, with respect to a reasonable computational time. Therefore, obtaining pulling speed closer to those which appear in the atomic force spectroscopy is possible. The newly implemented method has been tested for behavior in a microcanonical run to verify the influence of introduction of artificial constrains on keeping total energy of the system. Moreover, as time dependent artificial force was introduced, the thermostat behavior was tested. The new method was also tested via unfolding of the Fn3 domain of human contactin 1 protein and the I27 titin domain. Obtained results were compared with Gø‐like force field, all‐atom force field, and experimental results. © 2017 Wiley Periodicals, Inc.     

Efficient global optimization of reactive force‐field parameters

Reactive force fields make low‐cost simulations of chemical reactions possible. However, optimizing them for a given chemical system is difficult and time‐consuming. We present a high‐performance implementation of global force‐field parameter optimization, which delivers parameter sets of the same quality with much less effort and in far less time than before, and also offers excellent parallel scaling. We demonstrate these features with example applications targeting the ReaxFF force field. © 2015 Wiley Periodicals, Inc.