Implicit versus explicit solvent in free energy calculations of enzyme catalysis: Methyl transfer catalyzed by catechol O-methyltransferase

We compare free energy calculations for the methyl transfer reaction catalyzed by catechol O-methyltransferase using the quantum mechanical/molecular mechanical free energy method with implicit and explicit solvents. An analogous methylation reaction in a solution is also studied. For the explicit solvent model, we use the three-point transferable intermolecular potential model, and for the implicit model, we use the generalized Born molecular volume model as implemented in CHARMM. We find that activation and reaction free energies calculated with the two models are very similar, despite some structural differences that exist. A significant change in the polarization of the environment occurs as the reaction proceeds. This is more pronounced for the reaction in a solution than for the enzymatic reaction. For the enzymatic reaction, most of the changes take place in the protein rather than in the solvent, and, hence, the benefit of having an instantaneous relaxation of the solvent degrees of freedom is less pronounced for the enzymatic reaction than for the reaction in a solution. This is a likely reason why energies of the enzyme reaction are less sensitive to the choice of atomic radii than are energies of the reaction in a solution.     

The role of solvent fluctuations in hydrophobic assembly

We use a coarse-grained solvent model to study the self-assembly of two nanoscale hydrophobic particles in water. We show how solvent degrees of freedom are involved in the process. By using tools of transition path sampling, we elucidate the reaction coordinates describing the assembly. In accord with earlier expectations, we find that fluctuations of the liquid-vapor-like interface surrounding the solutes are significant, in this case leading to the formation of a vapor tunnel between the two solute particles. This tunnel accelerates assembly. While considering this specific model system, the approach we use illustrates a methodology that is broadly applicable.     

Extending the horizon: towards the efficient modeling of large biomolecular complexes in atomic detail

The application of evaluation of implicit solvent methods for the simulation of biomolecules is described. Detailed comparisons with explicit solvent are described for the modeling of peptide and proteins in continuum aqueous solvent. In addition, we are presenting new data on the simulation of DNA with implicit solvent and describe the development of a heterogeneous dielectric model for the simulation of integral membranes. The performance of implicit solvent simulations based on the GBMV generalized Born method is compared with explicit solvent simulations, and implications for the simulation of very large biomolecular complexes is discussed. We are anticipating that the work described herein will lead to new, efficient modeling tools that will allow the simulation of longer timescales and larger system sizes in order to meet current and future challenges by the experimental community.     

Theoretical studies of dissociative phosphoryl transfer in interconversion of phosphoenolpyruvate to phosphonopyruvate: solvent effects, thio effects, and implications for enzymatic reactions

The conversion of phosphoenolpyruvate (PEP) to phosphonopyruvate (P-pyr) is catalyzed by PEP mutase via a dissociative mechanism. In this work, we investigate the uncatalyzed reaction using ab initio methods, density functional theory, and the semiempirical MNDO/d method. Comparisons of geometries and relative energies of stationary points (minima and transition states) with density functional results indicate that the semiempirical method is reasonably accurate. Solvent effects are examined using implicit solvent models, including the recently extended smooth conductor-like screening model. Due to the large negative charge carried by the system, solvation is found to drastically alter the location and energy of stationary points along the dissociative reaction pathways. The influence of substituting a nonbridging phosphoryl oxygen by sulfur (thio effects) was also investigated. Implications of these results for the enzymatic reaction are discussed.     

Theoretical Study of the Intramolecular Proton Transfer in the Tautomers of Cytosine Assisted by Water

Ab initio MP2 and DFT studies on the tautomers of cytosine and the related hydrated tautomers have been carried out. The ground‐state structures of four tautomers of cytosine and related transition states were fully optimized. The vibrational frequency analysis was performed on all the optimized structures. Detailed intrinsic reaction coordinate (IRC) calculations were carried out to guarantee the optimized transition‐state structures being connected to the related tautomers. We obtained the relative stability order for the tautomers of cytosine and the related hydrated tautomers. In the isolated and hydrated condition, the bond types of C(2) O(7) and C(4) N(8) greatly affect the stability of the cytosine tautomers. Moreover, we have explored the influence of the water molecules on the intramolecular proton transfer between the keto and enol forms of the cytosine tautomers. The first water molecule obviously decreases the isomerization activation energy for the monohydrated cytosine tautomers. It is shown that the isomerization energy barrier changes only a little when the second and third water molecules are added in the reaction loop. The solvent effects have an obvious influence on the proton‐transfer barrier of the isolated cytosine. However, the solvent effects seem to be insignificant for the isomerization energy barriers of the monohydrated, dihydrated and trihydrated cytosine. The water molecule in these complexes can be looked on as the explicit water. Therefore, the explicit water model may be more credible to explore the intramolecular proton transfer, in comparison with the PCM which is the implicit water model.     

Bottom-up view of water network-mediated CO2 reduction using cryogenic cluster ion spectroscopy and direct dynamics simulations

The transition states of a chemical reaction in solution are generally accessed through exchange of thermal energy between the solvent and the reactants. As such, an ensemble of reacting systems approaches the transition state configuration of reactant and surrounding solvent in an incoherent manner that does not lend itself to direct experimental observation. Here we describe how gas-phase cluster chemistry can provide a detailed picture of the microscopic mechanics at play when a network of six water molecules mediates the trapping of a highly reactive "hydrated electron" onto a neutral CO(2) molecule to form a radical anion. The exothermic reaction is triggered from a metastable intermediate by selective excitation of either the reactant CO(2) or the water network, which is evidenced by the evaporative decomposition of the product cluster. Ab initio molecular dynamics simulations of energized CO(2)·(H(2)O)(6)(-) clusters are used to elucidate the nature of the network deformations that mediate intracluster electron capture, thus revealing the detailed solvent fluctuations implicit in the Marcus theory for electron-transfer kinetics in solution.     

Solvent reaction field potential inside an uncharged globular protein: a bridge between implicit and explicit solvent models?

The solvent reaction field potential of an uncharged protein immersed in simple point charge/extended explicit solvent was computed over a series of molecular dynamics trajectories, in total 1560 ns of simulation time. A finite, positive potential of 13-24 kbTec(-1) (where T=300 K), dependent on the geometry of the solvent-accessible surface, was observed inside the biomolecule. The primary contribution to this potential arose from a layer of positive charge density 1.0 A from the solute surface, on average 0.008 ec/A3, which we found to be the product of a highly ordered first solvation shell. Significant second solvation shell effects, including additional layers of charge density and a slight decrease in the short-range solvent-solvent interaction strength, were also observed. The impact of these findings on implicit solvent models was assessed by running similar explicit solvent simulations on the fully charged protein system. When the energy due to the solvent reaction field in the uncharged system is accounted for, correlation between per-atom electrostatic energies for the explicit solvent model and a simple implicit (Poisson) calculation is 0.97, and correlation between per-atom energies for the explicit solvent model and a previously published, optimized Poisson model is 0.99.     

Ab initio QM/MM study of excited state electron transfer between pyrene and 4,4′‐bis(dimethylamino)‐diphenylmethane with different solvent systems: Role of hydrogen bonding within solvent molecules

The exciplex is a charge transfer species formed in the process of electron transfer between an electron donor and an electron acceptor and hence is very sensitive to solvent polarity. In order to understand the role of solvent in exciplex formation between pyrene (PY) and 4,4′‐bis(dimethylamino)diphenylmethane (DMDPM), we used two types of solvent approximations: an implicit solvent model and an explicit solvent model. The difference in energies between the excited and the meta‐stable Frank–Condon state (ΔE) of the structures were assumed to correspond to the emission maximum of the exciplex in different solvents. The ΔE values show the trend of stabilization of the exciplex with an increase in solvent polarity. This trend in stabilization is substantially more prominent in the explicit solvent model than that with the implicit solvent model. The ΔE value obtained in methanol reflects equal stabilization compared to that in a more polar solvent, N,N‐dimethylformamide. This extra stabilization of the exciplex may be explained on the basis of the H‐bonding capability of the protic solvent, methanol. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

The use of a generalized born model for the analysis of protein conformational transitions: a comparative study with explicit solvent simulations for chemotaxis Y protein (CheY)

To investigate whether implicit solvent models are appropriate for mechanistic studies of conformational transition in proteins, a recently developed generalized Born model (GBSW) was applied to a small signaling protein, chemotaxis protein Y (CheY), with different combinations of the phosphorylation state and conformation of the system; the results were compared to explicit solvent simulations using a stochastic boundary condition. The subtle but distinct conformational transitions involved in CheY activation makes the system ideally suited for comparing implicit and explicit solvent models because these conformational transitions are potentially accessible in both types of simulations. The structural and dynamical properties analyzed include not only those localized to the active site region but also throughout the protein, such as sidechain methyl group order parameters, backbone hydrogen bonding lifetime and occupancy as well as principal components of the trajectories. Overall, many properties were well reproduced by the GBSW simulations when compared with the explicit solvent calculations, although a number of observations consistently point to the suggestion that the current parameterization of the GBSW model tends to overestimate hydrogen-bonding interactions involving both charged groups and (charge-neutral) backbone atoms. This deficiency led to overstabilization of certain secondary structural motifs and more importantly, qualitatively different behaviors for the active site groups (Thr 87, Ala 88, the beta4-alpha4 loop) in response to phosphorylation, when compared with explicit solvent simulations. The current study highlights the value of carrying out both explicit and implicit solvent simulations for complementary mechanistic insights in the analysis of conformational transition in biomolecules.     

Implementation and testing of stable, fast implicit solvation in molecular dynamics using the smooth-permittivity finite difference Poisson-Boltzmann method

A fast stable finite difference Poisson-Boltzmann (FDPB) model for implicit solvation in molecular dynamics simulations was developed using the smooth permittivity FDPB method implemented in the OpenEye ZAP libraries. This was interfaced with two widely used molecular dynamics packages, AMBER and CHARMM. Using the CHARMM-ZAP software combination, the implicit solvent model was tested on eight proteins differing in size, structure, and cofactors: calmodulin, horseradish peroxidase (with and without substrate analogue bound), lipid carrier protein, flavodoxin, ubiquitin, cytochrome c, and a de novo designed 3-helix bundle. The stability and accuracy of the implicit solvent simulations was assessed by examining root-mean-squared deviations from crystal structure. This measure was compared with that of a standard explicit water solvent model. In addition we compared experimental and calculated NMR order parameters to obtain a residue level assessment of the accuracy of MD-ZAP for simulating dynamic quantities. Overall, the agreement of the implicit solvent model with experiment was as good as that of explicit water simulations. The implicit solvent method was up to eight times faster than the explicit water simulations, and approximately four times slower than a vacuum simulation (i.e., with no solvent treatment).     

Mechanism of the Pechmann reaction: a theoretical study

One of the most widespread synthetic routes to coumarins is the condensation of esters and phenols via the Pechmann reaction. Despite the industrial and technological importance of the reaction, its mechanism is still poorly understood. We have explored several possible reaction paths by DFT calculations at the M05-2X/6-31+G* level. Amphoteric groups and the solvent have a crucial role in the frequent proton-transfer steps of the mechanisms; therefore, we have employed a mixed solvent model, where we combined the implicit PCM model together with an explicit water molecule placed at the actual proton transfer region. The Gibbs free-energy profiles of the possible routes suggest that three parallel channels (featuring water elimination, trans-esterification, and electrophilic attack) operate simultaneously. Enolic routes have prohibitively high activation barriers rendering these paths untenable. The calculated profiles indicate that in each feasible route the first elementary step has the highest activation energy. Reaction intermediates identified on the free-energy profiles can explain several experimental observations.     

Comparison of implicit solvent models for the simulation of protein-surface interactions

Empirical force field-based molecular simulations can provide valuable atomistic-level insights into protein-surface interactions in aqueous solution. While the implicit treatment of solvation effects is desired as a means of improving simulation efficiency, existing implicit solvent models were primarily developed for the simulation of peptide or protein behavior in solution alone, and thus may not be appropriate for protein interactions with synthetic material surfaces. The objective of this research was to calculate the change in free energy as a function of surface-separation distance for peptide-surface interactions using different empirical force field-based implicit solvation models (ACE, ASP, EEF1, and RDIE with the CHARMM 19 force field), and to compare these results with the same calculations conducted using density functional theory (DFT) combined with the self-consistent reaction field (SCRF) implicit solvation model. These comparisons show that distinctly different types of behavior are predicted with each implicit solvation method, with ACE providing the best overall agreement with DFT/SCRF calculations. These results also identify areas where ACE is in need of improvement for this application and provide a basis for subsequent parameter refinement.     

Generalized-ensemble simulations of the human parathyroid hormone fragment PTH(1-34)

A generalized-ensemble technique, multicanonical sampling, is used to study the folding of a 34-residue human parathyroid hormone fragment. An all-atom model of the peptide is employed and the protein-solvent interactions are approximated by an implicit solvent. Our results demonstrate that generalized-ensemble simulations are well suited to sample low-energy structures of such large polypeptides. Configurations with a root-mean-square deviation to the crystal structure of less than 1 A are found. Finally, we discuss limitations of our implicit solvent model.     

Application of the accelerated molecular dynamics simulations to the folding of a small protein

In this paper, we further explore the applicability of the accelerated molecular dynamics simulation method using a bias potential. The method is applied to both simple model systems and real multidimensional systems. The method is also compared to replica exchange simulations in folding a small protein, Trp cage, using an all atom potential for the protein and an implicit model for the solvent. We show that the bias potential method allows quick searches of folding pathways. We also show that the choice of the bias potential has significant influence on the efficiency of the bias potential method.     

Theoretical study of the effects of solvent environment on photophysical properties and electronic structure of paracyclophane chromophores

We use first-principles quantum-chemical approaches to study absorption and emission properties of recently synthesized distyrylbenzene (DSB) derivative chromophores and their dimers (two DSB molecules linked through a [2.2]paracyclophane moiety). Several solvent models are applied to model experimentally observed shifts and radiative lifetimes in Stokes nonpolar organic solvents (toluene) and water. The molecular environment is simulated using the implicit solvation models, as well as explicit water molecules and counterions. Calculations show that neither implicit nor explicit solvent models are sufficient to reproduce experimental observations. The contact pair between the chromophore and counterion, on the other hand, is able to reproduce the experimental data when a partial screening effect of the solvent is taken into account. Based on our simulations we suggest two mechanisms for the excited-state lifetime increase in aqueous solutions. These findings may have a number of implications for organic light-emitting devices, electronic functionalities of soluble polymers and molecular fluorescent labels, and their possible applications as biosensors and charge/energy conduits in nanoassemblies.     

Solvent Effect on The Equilibrium and Rate Constant of the Tautomeric Reaction in Nexium,Skelaxin, Aldara and Efavirenz Drugs: A Dft Study

Some drugs have two tautomeric structures in the liquid state and the tautomeric equilibrium is formed between these structures. The reaction rate and equilibrium constant of this reaction varies in different solvents. Thus, the determination of the appropriate solvent to separate tautomers is important. In this research, we used the DFT level of B3LYP and the 6-311++G** basis set to obtain the proper solvent for Nexium, Skelaxin, Aldara and Efavirenz drugs. All calculations were made above the melting point of the mentioned drugs, because these drugs are solid at room temperature. The solvent effect is included in the calculation utilizing the polarizable continuum model PCM. The transition state of the tautomeric reaction is determined using the quadratic synchronous transit (QST2) method. The geometry, energy, and dipole moment of transition states are analyzed in different solvent. The root mean square deviation (RMSD) analysis is performed to determine the degree of a structure deviation of tautomer 1 and tautomer 2 from the transition state in different solvents. It is found that the RMSD value for tatumer1 is higher than that for tautomer 2 in all studied drugs. The proper solvent for the separation of tautomers is determined from the analysis of thermodynamics and kinetics.     

Implicit solvent simulations of DNA and DNA-protein complexes: agreement with explicit solvent vs experiment

Molecular dynamics simulations of biomolecules with implicit solvent reduce the computational cost and complexity of such simulations so that longer time scales and larger system sizes can be reached. While implicit solvent simulations of proteins have become well established, the success of implicit solvent in the simulation of nucleic acids has not been fully established to date. Results obtained in this study demonstrate that stable and efficient simulations of DNA and a protein-DNA complex can be achieved with an implicit solvent model based on continuum dielectric electrostatics. Differences in conformational sampling of DNA with two sets of atomic radii that are used to define the dielectric interface between the solute and the continuum dielectric model of the solvent are investigated. Results suggest that depending on the choice of atomic radii agreement is either closer to experimental data or to explicit solvent simulations. Furthermore, partial conformational transitions toward A-DNA conformations when salt is added within the implicit solvent framework are observed.