Molecular Mechanics Potentials Research Articles

The dynamo library for molecular simulations using hybrid quantum mechanical and molecular mechanical potentials

The dynamo library for molecular simulations using hybrid quantum mechanical and molecular mechanical potentials

The generalized hybrid orbital method for combined quantum mechanical/molecular mechanical calculations: formulation and tests of the analytical derivatives

Hybrid quantum mechanical (QM) and molecular mechanical (MM) potentials are becoming increasingly important for studying condensed-phase systems but one of the outstanding problems in the field has been how to treat covalent bonds between atoms of the QM and MM regions. Recently, we presented a generalized hybrid orbital (GHO) method that was designed to tackle this problem for hybrid potentials using semiempirical QM methods [Gao et al. (1998) J Phys Chem A 102: 4714–4721]. We tested the method on some small molecules and showed that it performed well when compared to the purely QM or MM potentials. In this article, we describe the formalism for the determination of the GHO energy derivatives and then present the results of more tests aimed at validating the model. These tests, involving the calculation of the proton affinities of some model compounds and a molecular dynamics simulation of a protein, indicate that the GHO method will prove useful for the application of hybrid potentials to solution-phase macromolecular systems.

What Is the Solvation Number of Na+ in Ammonia? An Ab Initio QM/MM Molecular Dynamics Study

An ab initio molecular dynamics simulation based on combined quantum mechanical and molecular mechanical (QM/MM) potential was performed for Na+ in liquid ammonia. With this approach, many-body interactions that are very significant in determining the solvation number are modeled accurately by quantum mechanics. The method appears to resolve the discrepancy between many simulations that have predicted solvation numbers between 5 and 9. Although the solvation number of 5 obtained from our QM/MM simulation has not yet been confirmed by the experimental data, a detailed analysis of the simulation results together with a comparison of previous studies on known systems justifies this prediction.

Rotamer-Specific Potentials of Mean Force for Residue Pair Interactions

We present an approach for the development of knowledge-based mean-force potentials for representing residue−residue interactions in proteins at the amino acid level of resolution which take into account the rotamer states of the residues. The rotamer-specific potentials which consist of an additional correction term to the current database-derived statistical potentials are expressed in terms of distance-dependent mean force potentials (MFP). To describe the relative geometry of two residues we used a set of six distances between different pairs of atoms. The distant-dependent MFPs are calculated from computer simulations of each pair of amino acids at the atomic level using the weighted-histogram analysis method. The umbrella sampling for each of 52003 different rotamer pairs was performed with a force-bias Monte Carlo algorithm using molecular mechanics potentials with statistically derived restraint terms. Our simulations show that the MFPs are very sensitive to the rotamer states of the amino acid residues. Preliminary tests of the potential's performance show that it can reproduce side-chain packing with reasonable accuracy.

The dynamo library for molecular simulations using hybrid quantum mechanical and molecular mechanical potentials

The Dynamo module library has been developed for the simulation of molecular systems using hybrid quantum mechanical (QM) and molecular mechanical (MM) potentials. Dynamo is not a program package but is a library of Fortran 90 modules that can be employed by those interested in writing their own programs for performing molecular simulations. The library supports a range of different types of molecular calculation including geometry optimizations, reaction-path determinations and molecular dynamics and Monte Carlo simulations. This article outlines the general structure and capabilities of the library and describes in detail Dynamo's semiempirical QM/MM hybrid potential. Results are presented to indicate three particular aspects of this implementation—the handling of long-range nonbonding interactions, the nature of the boundary between the quantum mechanical and molecular mechanical atoms and how to perform path-integral hybrid-potential molecular dynamics simulations. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 1088–1100, 2000

Molecular dynamics simulation of nucleic acids: Successes, limitations, and promise

In the last five years we have witnessed a significant increase in the number publications describing accurate and reliable all-atom molecular dynamics simulations of nucleic acids. This increase has been facilitated by the development of fast and efficient methods for treating the long-range electrostatic interactions, the availability of faster parallel computers, and the development of well-validated empirical molecular mechanical force fields. With these technologies, it has been demonstrated that simulation is not only capable of consistently reproducing experimental observations of sequence specific fine structure of DNA, but also can give detailed insight into prevalent problems in nucleic acid structure, ion association and specific hydration of nucleic acids, polyadenine tract bending, and the subtle environmental dependence of the A-DNA-B-DNA duplex equilibrium. Despite the advances, there are still issues with the methods that need to be resolved through rigorous controlled testing. In general, these relate to deficiencies of the underlying molecular mechanical potentials or applied methods (such as the imposition of true periodicity in Ewald simulations and the need for energy conservation), and significant limits in effective conformational sampling. In this perspective, we provide an overview of our experiences, provide some cautionary notes, and provide recommendations for further study in molecular dynamics simulation of nucleic acids.

Hydrogen-bonding interactions in the active site of a low molecular weight protein-tyrosine phosphatase

Molecular dynamics simulation of the Michaelis complex, phospho-enzyme intermediate, and the wild-type and C12S mutant have been carried out to examine hydrogen-bonding interactions in the active site of the bovine low molecular weight protein-tyrosine phosphatase (BPTP). It was found that the Sγ atom of the nucleophilic residue Cys-12 is ideally located at a position opposite from the phenylphosphate dianion for an inline nucleophilic substitution reaction. In addition, electrostatic and hydrogen-bonding interactions from the backbone amide groups of the phosphate-binding loop strongly stabilize the thiolate anion, making Cys-12 ionized in the active site. In the phospho-enzyme intermediate, three water molecules are found to form strong hydrogen bonds with the phosphate group. In addition, another water molecule can be identified to form bridging hydrogen bonds between the phosphate group and Asp-129, which may act as the nucleophile in the subsequent phosphate hydrolysis reaction, with Asp-129 serving as a general base. The structural difference at the active site between the wild-type and C12S mutant has been examined. It was found that the alkoxide anion is significantly shifted toward one side of the phosphate binding loop, away from the optimal position enjoyed by the thiolate anion of the wild-type enzyme in an SN2 process. This, coupled with the high pKa value of an alcoholic residue, makes the C12S mutant catalytically inactive. These molecular dynamics simulations provided details of hydrogen bonding interactions in the active site of BPTP, and a structural basis for further studies using combined quantum mechanical and molecular mechanical potential to model the entire dephosphorylation reaction by BPTP. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 1192–1203, 2000

Prediction of loop geometries using a generalized born model of solvation effects

We have carried out an extensive exploration of the possibility of predicting the structure of long loops in proteins, using an 8- and a 12-residue loop in ribonuclease A as models. The native X-ray structure is used as a template while allowing for template flexibility; this makes our work relevant to the problem of homology modeling in which the template is not precisely known. Energies are calculated with the AMBER* and AMBER94 molecular mechanics potentials and the generalized Born continuum solvation model; and conformational space is sampled by means of a combination of Monte Carlo and molecular dynamics methods. Our AMBER94 results demonstrate that we can successfully generate loops with low root-mean-square deviations from the native as well as excellent energetic rankings. Proteins 1999;35:173–183. © 1999 Wiley-Liss, Inc.

Prediction of loop geometries using a generalized born model of solvation effects

We have carried out an extensive exploration of the possibility of predicting the structure of long loops in proteins, using an 8- and a 12-residue loop in ribonuclease A as models. The native X-ray structure is used as a template while allowing for template flexibility; this makes our work relevant to the problem of homology modeling in which the template is not precisely known. Energies are calculated with the AMBER* and AMBER94 molecular mechanics potentials and the generalized Born continuum solvation model; and conformational space is sampled by means of a combination of Monte Carlo and molecular dynamics methods. Our AMBER94 results demonstrate that we can successfully generate loops with low root-mean-square deviations from the native as well as excellent energetic rankings.

Binding Energy of F(H2O)- and the Simulation of Fluoride Water Clusters Using a Hybrid QM/MM (Fluctuating Charge) Potential

High-level ab initio calculations have been used to determine the binding energy of F(H2O)-. A value of −27.3 kcal/mol has been obtained, which is considerably greater than the experimental value near −23 kcal/mol. The new theoretical value is used to parametrize a hybrid quantum mechanical (QM)/molecular mechanical (MM) potential in which F- is described at a high level of quantum mechanics and H2O is modeled with a fluctuating charge MM potential. Static and dynamic calculations of F(H2O)4- are carried out using this hybrid QM/MM potential. Static calculations using both full electronic structure methods and the hybrid potential predict a range of interior and surface structures within 2 kcal/mol, while molecular dynamics simulation at 300 K using the hybrid potential suggests that a range of structures will be observed.

Incorporating density functional potential in classical molecular dynamics simulation

UNDERSTANDING the properties of reactions in condensed phases, e.g. in solutions or in enzymes, is one of the most challenging questions to both physical chemists and biological chemists. Classical molecular mechanics potential, though widely tested and employed in molecular dynamics simulation, is not feasible to simulating the reaction process where the quantum effects are dominative. Several hybrid approaches have been proposed to combine quantum mechanics (QM) potential with molecular mechanics (MM) potential, in which the reaction site is treated quantum mechanically, and the environment classically.The substantial differences among those hybrid strategies are the QM models employed to treat reaction site, which includes empirical VB models, semi-empirical molecular orbital models (MNDO, AM1,PM3), Hartree-Fock models, etc. Recently, density functional (DF) theory has been tested as the quantum mechanics model in the hybrid method to treat the reaction site. As another 'ab initial' theory,DF theory

Self-Consistent Reaction Field Calculations of Nonequilibrium Solvent Effects on Proton Transfer Processes through Low-Barrier Hydrogen Bonds

We investigate dynamic solvent effects on proton transfer reactions in the strongly hydrogen-bonded hydroxyl−water model system by using a self-consistent nonequilibrium reaction field method. The initial motivation for the present work lies in the results of a recently reported molecular dynamics simulation for the same system in aqueous solution, carried out through combined density functional and molecular mechanics potentials. Such a study has confirmed that proton transfer occurs in an essentially frozen environment and that solvent fluctuations may play a crucial role in the reaction dynamics. Nevertheless, owing to the use of effective charge water models in molecular dynamics simulations, the effect of solvent electronic polarization, which can be assumed to respond instantaneously to solute charge modifications, cannot be accounted for explicitly. Our main goal in the present study is to analyze such an effect in the effective energy profile instantaneously experienced by the proton, using for th...

Born−Oppenheimer ab Initio QM/MM Dynamics Simulations of Na+and K+in Water: From Structure Making to Structure Breaking Effects

The description of nonadditive contributions in the first hydration shell of Na+ and K+ has been improved by performing molecular dynamics simulations based on combined ab initio quantum mechanical and molecular mechanical potentials. The active-site region, the first hydration sphere of ions, is treated by Born−Oppenheimer ab initio quantum mechanics, while the environment is described by classical pair potentials. The average coordination numbers obtained by this high accuracy method, with valence double-ζ basis sets for water and Los Alamos ECP plus DZ basis sets for cations, lead to a lower value of 5.6 ± 0.3 for Na+ and a higher value of 8.3 ± 0.3 for K+, respectively, compared to the corresponding values of 6.5 ± 0.2 and 7.8 ± 0.2 resulting from pair potentials. The effects of nonadditive terms are also found to play a significant role in the preferential orientation of water molecules within the first hydration shell of Na+ and K+. The experimentally observed “structure-breaking” effects of K+ are well reflected and explained on a molecular basis by the simulation results.

Proton transport along water chains and NADH hydride transfer in solution

AbstractThis paper presents simulations of two biologically important processes involving proton or hydride transfer reactions. The first process is proton transport along a protonated chain of three water molecules. This process is induced with a linearly increasing external electric field. The multiconfigurational molecular dynamics with quantum transitions (MC‐MDQT) method is utilized to calculate the real‐time nonequilibrium quantum dynamics of this process. The results illustrate that nonadiabatic effects play an important role in the proton dynamics for water chains under certain nonequilibrium conditions. The second process discussed in this paper is the hydride transfer reaction from ethanol to an NAD+ analog (1‐methyl‐nicotinamide) in water with a divalent zinc ion catalyst. The structures, relative energies, and charge distributions are calculated for the reactant, product, and transition state of a complex including the NAD+ analog, ethanol, zinc, and three water molecules at the Hartree‐Fock level with a polarized valence double zeta basis set. This information is utilized to parametrize an augmented molecular mechanical potential, which is implemented to calculate the classical free energy curve for this reaction in water. The results indicate that solvation effects significantly alter the energetics of this reaction.

Solvent effects on the nπ* transition of pyrimidine in aqueous solution

A hybrid quantum mechanical and molecular mechanical potential is used in Monte Carlo simulations to examine the solvent effects on the electronic excitation energy for the n→π* transition of pyrimidine in aqueous solution. In the present study, the pyrimidine molecule is described by the semi-empirical AM1 model, while the solvent molecules are treated classically. Two sets of calculations are performed: the first involves the use of the pairwise three-point charge TIP3P model for water, and the second computation employs a polarizable many-body potential for the solvent. The latter calculation takes into account the effect of solvent polarization following the solute electronic excitation, and makes a correction to the energies determined using pairwise potentials, which neglects such fast polarization effects and overestimates the solute-solvent interactions on the Franck-Condon excited states. Our simulation studies of pyrimidine in water indicate that the solvent charge redistribution following the solute electronic excitation makes modest corrections (about −130␣cm−1) to the energy predicted by using pairwise potentials. Specific hydrogen bonding interactions between pyrimidine and water are important for the prediction of solvatochromic shifts for pyrimidine. The computed n→π* blue shift is 2275±110 cm−1, which may be compared with the experimental value (2700 cm−1) from isooctane to water.

Solvation of Ca2+ in Water Studied by Born−Oppenheimer ab Initio QM/MM Dynamics

Molecular dynamics simulations based on combined ab initio molecular quantum mechanics and molecular mechanical potentials are applied to investigate the structural and dynamical properties of calcium ion solvated in liquid water. The region of highest interest, the hydration sphere of the calcium ion, is investigated by Born−Oppenheimer ab initio quantum mechanics, while the rest of the system is described by classical pair potentials. A coordination number of 8.3 is found by this high-level QM/MM method with a double-ζ basis set, in contrast to 9.2 obtained by classical pair potential simulations. Dynamical properties are related to the solvate structure. Smaller basis sets have been used to study the influence of basis sets used in the quantum mechanical part.

Development of a Potential Surface for Simulation of Proton and Hydride Transfer Reactions in Solution: Application to NADH Hydride Transfer

This paper presents a new augmented molecular mechanical potential that incorporates significant quantum mechanical effects for proton and hydride transfer reactions in solution and in enzymes. The solvent is treated explicitly, specified covalent bonds in the solute are allowed to break and form, and the charge distribution of the solute is allowed to vary smoothly from that of the reactant to that of the product during the reaction. Moreover, in order to incorporate changes in bond order and hybridization, an efficient constraint dynamics method is combined with switching functions to smoothly vary the structure of the complex from the reactant to the product structure during the reaction. This new methodology is applied to model nicotinamide adenine dinucleotide (NADH) hydride transfer reactions, in particular to the oxidation of ethanol by the NAD+ analog 1-methyl-nicotinamide in acetonitrile and in water. Both cis and trans orientations of the NADH amide sidearm and both protonated and deprotonated forms of the substrate are studied. The structures and charge distributions of the model complexes are obtained from ab initio gas phase geometry optimizations at the Hartree−Fock 6-31G* level and are utilized to parametrize the potential energy surface. Classical free energy curves in both acetonitrile and water are calculated in order to illustrate the solvent effects on the energy gap between the reactant and the product states. The radial distribution functions between the solute and the water molecules together with the orientational distributions of the hydration shell water molecules are also calculated in order to elucidate the nature and extent of hydrogen bonding between the solvent and the solute.

Molecular dynamics simulations of elementary chemical processes in liquid water using combined density functional and molecular mechanics potentials. I. Proton transfer in strongly H-bonded complexes

The first molecular dynamics (MD) simulation of a chemical process in solution with an ab initio description of the reactant species and a classical representation of the solvent is presented. We study the dynamics of proton (deuterium) transfer in strongly hydrogen-bonded systems characterized by an energy surface presenting a double well separated by a low activation barrier. We have chosen the hydroxyl-water complex in liquid water to analyze the coupling between the reactive system and the environment. The proton is transferred from one well to the other with a frequency close to 1 ps−1 which is comparable to the low-frequency band associated to hindered translations, diffusional translation and reorientation of water molecules in water. The proton transfer takes place in 20–30 fs whereas the solvent response is delayed by about 50 fs. Therefore, the reaction occurs in an essentially frozen-solvent configuration. In principle, this would produce a barrier increase with respect to the equilibrium reaction path. However, solvent fluctuations play a substantial role by catalyzing the proton transfer. The solvent relaxation time after proton transfer has been evaluated. Since it falls in the same time scale than the reactive events (0.6 ps) it substantially influences the proton dynamics. The present study is intended to model charge transfer processes in polar media having a low activation barrier for which many reactive events may be predicted in a MD simulation. The case of reactions with large activation barriers would require the use of special techniques to simulate rare events. But still in that case, hybrid QM/MM simulations represent a suitable tool to analyze reaction dynamics and non-equilibrium solvent effects in solution chemistry.

Molecular dynamics simulations of elementary chemical processes in liquid water using combined density functional and molecular mechanics potentials. II. Charge separation processes

A new approach to carry out molecular dynamics simulations of chemical reactions in solution using combined density functional theory/molecular mechanics potentials is presented. We focus our attention on the analysis of reactive trajectories, dynamic solvent effects and transmission coefficient rather than on the evaluation of free energy which is another important topic that will be examined elsewhere. In a previous paper we have described the generalities of this hybrid molecular dynamics method and it has been employed to investigate low energy barrier proton transfer process in water. The study of processes with activation energies larger than a few kT requires the use of specific techniques adapted to “rare events” simulations. We describe here a method that consists in the simulation of short trajectories starting from an equilibrated transition state in solution, the structure of which has been approximately established. This calculation is particularly efficient when carried out with parallel computers since the study of a reactive process is decomposed in a set of short time trajectories that are completely independent. The procedure is close to that used by other authors in the context of classical molecular dynamics but present the advantage of describing the chemical system with rigorous quantum mechanical calculations. It is illustrated through the study of the first reaction step in electrophilic bromination of ethylene in water. This elementary process is representative of many charge separation reactions for which static and dynamic solvent effects play a fundamental role.

Vibrational dynamics of the CH stretching mode of H-terminated diamond surfaces

The vibrational dynamics of hydrogen on low-index diamond surfaces is studied by the molecular dynamics method using an empirical Molecular Mechanics (MM3) potential. We find that the CH stretching peak positions in the vibrational spectra of hydrogen are sensitive to the surface structure and can be used for the experimental in situ analysis of the growing CVD diamond phase. The differences in the spectral features corresponding to the CH bending vibrations have been correlated with the results of the vibrational energy relaxation rate estimates. We find that the major contributions to the lifetimes of the excited CH stretching states come from the anharmonic coupling between the CH stretching and CCH bending vibration modes. The latter is highly coupled with the substrate phonons which leads to the formation of broad spectral regions associated with CCH bending vibrations. The dynamic analysis of the motion induced by the symmetric and antisymmetric stretching excitation on C{100} (2 × 1) H surface have been performed and the reasons for the unstability of the pure antisymmetric vibrations are discussed.