Absolute Free Energy Research Articles

VOLUMETRIC PROPERTIES AND VISCOSITIES OF ACETIC ACID WITH ETHYLENE GLYCOL AND DIETHYLENE GLYCOL AT TEMPERATURES FROM 303.15 TO 323.15 K

Densities and viscosities of the binary mixtures of acetic acid with ethylene glycol and diethylene glycol were measured over the entire range of composition at five temperatures T = 303.15, 308.15, 313.15, 318.15, and 323.15 K. The excess molar volumes and viscosity deviations were calculated and fitted to the Redlich-Kister type polynomial equation. The viscosity data reported herein were used to examine the modeling capabilities of viscosity equations based on Eyring's absolute reaction rate theory and excess Gibbs free energy functions, namely, the Eyring-Van Laar, the Eyring-Scatchard and Hamer, and the Eyring-UNIQUAC equations. Some one-parameter models such as the Fang and He equation and the Grunberg and Nissan equation were also tested.

Absolute free energies of biomolecules from unperturbed ensembles

Computing the absolute free energy of a macromolecule's structural state, F, is a challenging problem of high relevance. This study presents a method that computes F using only information from an unperturbed simulation of the macromolecule in the relevant conformational state, ensemble, and environment. Absolute free energies produced by this method, dubbed Valuation of Local Configuration Integral with Dynamics (VALOCIDY), enable comparison of alternative states. For example, comparing explicitly solvated and vaporous states of amino acid side-chain analogs produces solvation free energies in good agreement with experiments. Also, comparisons between alternative conformational states of model heptapeptides (including the unfolded state) produce free energy differences in agreement with data from μs molecular-dynamics simulations and experimental propensities. The potential of using VALOCIDY in computational protein design is explored via a small design problem of stabilizing a β-turn structure. When VALOCIDY-based estimation of folding free energy is used as the design metric, the resulting sequence folds into the desired structure within the atomistic force field used in design. The VALOCIDY-based approach also recognizes the distinct status of the native sequence regardless of minor details of the starting template structure, in stark contrast with a traditional fixed-backbone approach.

Molecular Recognition in a Diverse Set of Protein–Ligand Interactions Studied with Molecular Dynamics Simulations and End-Point Free Energy Calculations

End-point free energy calculations using MM-GBSA and MM-PBSA provide a detailed understanding of molecular recognition in protein-ligand interactions. The binding free energy can be used to rank-order protein-ligand structures in virtual screening for compound or target identification. Here, we carry out free energy calculations for a diverse set of 11 proteins bound to 14 small molecules using extensive explicit-solvent MD simulations. The structure of these complexes was previously solved by crystallography and their binding studied with isothermal titration calorimetry (ITC) data enabling direct comparison to the MM-GBSA and MM-PBSA calculations. Four MM-GBSA and three MM-PBSA calculations reproduced the ITC free energy within 1 kcal·mol(-1) highlighting the challenges in reproducing the absolute free energy from end-point free energy calculations. MM-GBSA exhibited better rank-ordering with a Spearman ρ of 0.68 compared to 0.40 for MM-PBSA with dielectric constant (ε = 1). An increase in ε resulted in significantly better rank-ordering for MM-PBSA (ρ = 0.91 for ε = 10), but larger ε significantly reduced the contributions of electrostatics, suggesting that the improvement is due to the nonpolar and entropy components, rather than a better representation of the electrostatics. The SVRKB scoring function applied to MD snapshots resulted in excellent rank-ordering (ρ = 0.81). Calculations of the configurational entropy using normal-mode analysis led to free energies that correlated significantly better to the ITC free energy than the MD-based quasi-harmonic approach, but the computed entropies showed no correlation with the ITC entropy. When the adaptation energy is taken into consideration by running separate simulations for complex, apo, and ligand (MM-PBSAADAPT), there is less agreement with the ITC data for the individual free energies, but remarkably good rank-ordering is observed (ρ = 0.89). Interestingly, filtering MD snapshots by prescoring protein-ligand complexes with a machine learning-based approach (SVMSP) resulted in a significant improvement in the MM-PBSA results (ε = 1) from ρ = 0.40 to ρ = 0.81. Finally, the nonpolar components of MM-GBSA and MM-PBSA, but not the electrostatic components, showed strong correlation to the ITC free energy; the computed entropies did not correlate with the ITC entropy.

Absolute Free Energy of Binding and Entropy of the FKBP12-FK506 Complex: Effects of the Force Field.

The hypothetical scanning molecular dynamics (HSMD) method combined with thermodynamic integration (HSMD-TI) has been extended recently for calculating ΔA(0)-the absolute free energy of binding of a ligand to a protein. With HSMD-TI, ΔA(0) is obtained in a new way as a sum of several components, among them is ΔSligand-the change in the conformational entropy as the ligand is transferred from the bulk solvent to the active site-this entropy is obtained by a specific reconstruction procedure. This unique aspect of HSMD (which is useful in rational drug design) is in particular important for treating large ligands, where ΔSligand might be significant. Technically, one should verify that the results for ΔSligand converge-a property that might become more difficult for large ligands; therefore, studying ligands of increasing size would define the range of applicability of HSMD-TI for binding. In this paper, we check the performance of HSMD-TI by applying it to the relatively large ligand FK506 (126 atoms) complexed with the protein FKBP12, where ΔA(0) = -12.8 kcal/mol is known experimentally as well as the crystal structure of the complex. This structure was initially equilibrated by carrying out a 100 ns molecular dynamics trajectory, where the system is modeled by the AMBER force field, TIP3P water, and Particle Mesh Ewald. HSMD-TI calculations were carried out in three conformational regions defined by the intervals [0.2,2], [2,5], and [5,100] ns along the trajectory, where local equilibration of the total energy has been observed; we obtained ΔA(0) = -13.6 ± 1.1, -16.6 ± 1.4, and -16.7 ± 1.4 kcal/mol, respectively indicating the following: (1) The second and third regions belong to the same conformational subspace of the complex, which is different from the [0.2,2] ns subspace. (2) The unsatisfactory result for ΔA(0) obtained in the well equilibrated (hence theoretically preferred) latter regions reflects the nonperfect modeling used, which however (3) has led to the experimental ΔA(0) in the [0.2,2] ns region close to the crystal structure. Keeping the complex near its crystal structure has been a successful approach in the literature. To check this avenue further, we applied harmonic restraints on backbone atoms and obtained unsatisfactory results for ΔA(0), suggesting that implementation of this approach is not straightforward. Converging results for ΔSligand were obtained in all regions, where the result ΔSligand([0.2,2]) = 7.1 ± 1.2 kcal/mol is less region dependent than ΔA(0) and is relatively large probably due to the large ligand.

A comparative study of methods to compute the free energy of an ordered assembly by molecular simulation

We present a comparative study of methods to compute the absolute free energy of a crystalline assembly of hard particles by molecular simulation. We consider all combinations of three choices defining the methodology: (1) the reference system: Einstein crystal (EC), interacting harmonic (IH), or r(-12) soft spheres (SS); (2) the integration path: Frenkel-Ladd (FL) or penetrable ramp (PR); and (3) the free-energy method: overlap-sampling free-energy perturbation (OS) or thermodynamic integration (TI). We apply the methods to FCC hard spheres at the melting state. The study shows that, in the best cases, OS and TI are roughly equivalent in efficiency, with a slight advantage to TI. We also examine the multistate Bennett acceptance ratio method, and find that it offers no advantage for this particular application. The PR path shows advantage in general over FL, providing results of the same precision with 2-9 times less computation, depending on the choice of a common reference. The best combination for the FL path is TI+EC, which is how the FL method is usually implemented. For the PR path, the SS system (with either TI or OS) proves to be most effective; it gives equivalent precision to TI+FL+EC with about 6 times less computation (or 12 times less, if discounting the computational effort required to establish the SS reference free energy). Both the SS and IH references show great advantage in capturing finite-size effects, providing a variation in free-energy difference with system size that is about 10 times less than EC. This result further confirms previous work for soft-particle crystals, and suggests that free-energy calculations for a structured assembly be performed using a hybrid method, in which the finite-system free-energy difference is added to the extrapolated (1/N→0) absolute free energy of the reference system, to obtain a result that is nearly independent of system size.

Structure-Based Virtual Screening and Molecular Dynamic Simulation Studies to Identify Novel Cytochrome bc1 Inhibitors as Antimalarial Agents

Cytochrome bc1 (EC 1.10.2.2, bc1) is an essential component of the cellular respiratory chain, which catalyzes electron transfer from quinol to cytochrome c and concomitantly the translocation of protons across the membrane. It has been identified as a promising target in malaria parasites. The structure-based pharmacophore modelling and molecular dynamic simulation approach have been employed to identify novel inhibitors of cytochrome bc1. The best structure-based pharmacophore hypothesis (Hypo1) consists of one hydrogen bond acceptor (HBA), one general hydrophobic (HY), and two hydrophobic aromatic features (HYAr). Further, hydrogen interactions and hydrophobic interactions of known potent inhibitors with cytochrome bc1 were compared with Hypo1, which showed that the Hypo1 has good predictive ability. The validated Hypo1 was used to screen the chemical databases. The hits obtained were subsequently subjected to the molecular docking analysis to identify false-positive hits. Moreover, the molecular docking results were further validated by molecular dynamics simulations. Binding-free energy analysis using MM-GBSA method reveals that the van der Waals interactions and the electrostatic energy provide the basis for favorable absolute free energy of the complex. The five virtual hits were identified as possible candidates for the designing of potent cytochrome bc1 inhibitors.

Temperature Integration: An efficient procedure for calculation of free energy differences

We propose a method, Temperature Integration, which allows an efficient calculation of free energy differences between two systems of interest, with the same degrees of freedom, which may have rough energy landscapes. The method is based on calculating, for each single system, the difference between the values of lnZ at two temperatures, using a Parallel Tempering procedure. If our two systems of interest have the same phase space volume, they have the same values of lnZ at high-T, and we can obtain the free energy difference between them, using the two single-system calculations described above. If the phase space volume of a system is known, our method can be used to calculate its absolute (versus relative) free energy as well. We apply our method and demonstrate its efficiency on a “toy model” of hard rods on a 1-dimensional ring.

Aluminum Hydride Separation Using N-Alkylmorpholine

We describe experimental and theoretical studies of several amine·alane adducts for alane separation. First, N-alkylmorpholine·alane adducts (NMM·AlH3 and NEM·AlH3; NMM = N-methylmorpholine, NEM = N-ethylmorpholine) were synthesized and characterized by NMR, IR, and XRD studies. Because of the bifunctionality (or dual coordination mode) of N-alkylmorpholine, NMM·AlH3 and NEM·AlH3 exhibit significantly improved thermal stability compared with the related amine·alane adducts. In the solid state, both NMM·AlH3 and NEM·AlH3 are polymers, which readily dissociate into monomers in donor solvents, as suggested by IR spectroscopy. In addition, the cost- and energy-effective transamination of (amine)2·AlH3 with NMM (or NEM) has been achieved. Because of the fast reaction kinetics, the transamination reaction could be combined with hydrogenation of Al metal to prepare NMM·AlH3 in a single step, further improving the efficiency of the process. Moreover, the thermal decomposition pathways of NMM·AlH3 and NEM·AlH3 have been elucidated. While NMM·AlH3 decomposes to Al metal directly, NEM·AlH3 can be selectively decomposed to give AlH3 under certain conditions. The dramatically different thermal properties of N-alkylmorpholine·AlH3 could be attributed to the different steric hindrance and basicity of N-alkylmorpholine compounds. Compared with the Et3N/Et3N·AlH3 process, our new approach using N-alkylmorpholine significantly improves the kinetics, selectivity, yields, and energy efficiency of AlH3 recovery. Lastly, theoretical calculations of molecular geometries, absolute free energies, Al–H vibrational frequencies, and thermodynamics of amine·alane adducts with different structures are in good agreement with experimental observations and provide further information for the interactions between amines and AlH3.

Fast and accurate generation of ab initio quality atomic charges using nonparametric statistical regression

We introduce a class of partial atomic charge assignment method that provides ab initio quality description of the electrostatics of bioorganic molecules. The method uses a set of models that neither have a fixed functional form nor require a fixed set of parameters, and therefore are capable of capturing the complexities of the charge distribution in great detail. Random Forest regression is used to build separate charge models for elements H, C, N, O, F, S, and Cl, using training data consisting of partial charges along with a description of their surrounding chemical environments; training set charges are generated by fitting to the b3lyp/6-31G* electrostatic potential (ESP) and are subsequently refined to improve consistency and transferability of the charge assignments. Using a set of 210 neutral, small organic molecules, the absolute hydration free energy calculated using these charges in conjunction with Generalized Born solvation model shows a low mean unsigned error, close to 1 kcal/mol, from the experimental data. Using another large and independent test set of chemically diverse organic molecules, the method is shown to accurately reproduce charge-dependent observables--ESP and dipole moment--from ab initio calculations. The method presented here automatically provides an estimate of potential errors in the charge assignment, enabling systematic improvement of these models using additional data. This work has implications not only for the future development of charge models but also in developing methods to describe many other chemical properties that require accurate representation of the electronic structure of the system.

Absolute Single-Ion Solvation Free Energy Scale in Methanol Determined by the Lithium Cluster-Continuum Approach

Absolute solvation free energy of the lithium cation in methanol was calculated by the cluster-continuum quasichemical theory of solvation. Clusters with up to five methanol molecules were investigated using X3LYP, MP2, and MP4 methods with DZVP, 6-311+G(2df,2p), TZVPP+diff, and QZVPP+diff basis sets and including the cluster solvation through the PCM and SMD continuum models. Our calculations have determined a value of -118.1 kcal mol(-1) for the solvation free energy of the lithium, in close agreement with a value of -116.6 kcal mol(-1) consistent with the TATB assumption. Using data of solvation and transfer free energy of a pair of ions, electrode potentials and pKa, we have obtained the solvation free energy of 25 ions in methanol. Our analysis leads to a value of -253.6 kcal mol(-1) for the solvation free energy of the proton, which can be compared with the value of -263.5 kcal mol(-1) obtained by Kelly et al. using the cluster pair approximation. Considering that this difference is due to the methanol surface potential, we have estimated that it corresponds to -0.429 V.

Toward the accurate calculation of pKa values in water and acetonitrile

We present a simple approach for the calculation of accurate pKa values in water and acetonitrile based on the straightforward calculation of the gas-phase absolute free energies of the acid and conjugate base with use of only a continuum solvation model to obtain the corresponding solution-phase free energies. Most of the error in such an approach arises from inaccurate differential solvation free energies of the acid and conjugate base which is removed in our approach using a correction based on the realization that the gas-phase acidities have only a small systematic error relative to the dominant systematic error in the differential solvation. The methodology is outlined in the context of the calculation of a set of neutral acids with water as the solvent for a reasonably accurate electronic structure level of theory (DFT), basis set, and implicit solvation model. It is then applied to the comparison of results for three different hybrid density functionals to illustrate the insensitivity to the functional. Finally, the approach is applied to the comparison of results for sets of neutral acids and protonated amine cationic acids in both aqueous (water) and nonaqueous (acetonitrile) solvents. The methodology is shown to generally predict the pKa values for all the cases investigated to within 1 pH unit so long as the differential solvation error is larger than the systematic error in the gas-phase acidity calculations. Such an approach is rather general and does not have additional complications that would arise in a cluster-continuum method, thus giving it strength as a simple high-throughput means to calculate absolute pKa values. This article is part of a Special Issue entitled: Metals in Bioenergetics and Biomimetics Systems.

Charging Free Energy Calculations Using the Generalized Solvent Boundary Potential (GSBP) and Periodic Boundary Condition: A Comparative Analysis Using Ion Solvation and Oxidation Free Energy in Proteins

Free energy simulations using a finite sphere boundary condition rather than a periodic boundary condition (PBC) are attractive in the study of very large biomolecular systems. To understand the quantitative impact of various approximations in such simulations, we compare charging free energies in both solution and protein systems calculated in a linear response framework with the Generalized Solvent Boundary Potential (GSBP) and PBC simulations. For simple ions in solution, we find good agreements between GSBP and PBC charging free energies, once the relevant correction terms are taken into consideration. For PBC simulations with the particle-mesh-Ewald for long-range electrostatics, the contribution (ΔG(P-M)) due to the use of a particle rather than molecule based summation scheme in real space is found to be significant, as pointed out by Hünenberger and co-workers. For GSBP, when the inner region is close to be charge neutral, the key correction is the overpolarization of water molecules at the inner/outer dielectric boundary; the magnitude of the correction (ΔG(s-pol)), however, is relatively small. For charging (oxidation) free energy in proteins, the situation is more complex, although good agreement between GSBP and PBC can still be obtained when care is exercised. The smooth dielectric boundary approximation inherent to GSBP tends to make significant errors when the inner region is featured with a high net charge. However, the error can be corrected with Poisson-Boltzmann calculations using snapshots from GSBP simulations in a straightforward and robust manner. Because of the more complex charge and solvent distributions, the magnitudes of ΔG(P-M) and ΔG(s-pol) in protein simulations appear to be different from those derived for solution simulations, leading to uncertainty in directly comparing absolute charging free energies from PBC and GSBP simulations for protein systems. The relative charging/oxidation free energies, however, are robust. With the linear response approximation, for the specific protein system (CueR) studied, the effect of freezing the protein structure in the outer region is found to be small, unless a very small (8 Å) inner region is used; even in the latter case, the result is substantially improved when the nearby metal binding loop is allowed to respond to metal oxidation. The implications of these results to the applicability of GSBP to complex biomolecules and in ab initio QM/MM simulations are discussed.

N-Alkylpyrrolidine·Alane Compounds for Energy Applications

Aluminum hydride (AlH3) has high gravimetric and volumetric hydrogen densities and is thus a promising hydrogen storage material. As part of our effort to develop a cost-effective regeneration pathway for AlH3, we report the synthesis and characterization of N-alkylpyrrolidine·alane complexes (NMPy)2·AlH3, NMPy·AlH3, and NEPy·AlH3 (NMPy = N-methylpyrrolidine, NEPy = N-ethylpyrrolidine); the reversible formation of (NMPy)2·AlH3 from titanium-doped aluminum metal (denoted as Al*), H2 gas, and NMPy; and thermal decomposition studies of these alane adducts. Depending on the stoichiometric ratios of NMPy to AlH3, both the 2:1 complex (NMPy)2·AlH3 and the 1:1 complex NMPy·AlH3 can be selectively synthesized by direct reactions of NMPy with AlH3, whereas NEPy gives only the 1:1 adduct NEPy·AlH3 regardless of the ratio of NEPy to AlH3. In addition, the reversible formation of (NMPy)2·AlH3 from titanium-doped aluminum powder (Al*) and NMPy under a H2 pressure of 1000 psi was observed, while no alane formation was detected with NEPy. Theoretical calculations of the molecular geometries and absolute free energies are in good agreement with experimental observations, and indicate that the dramatic differences between NMPy and NEPy are caused by the steric effects imposed by the alkyl group (methyl or ethyl) on the pyrrolidine ring. Finally, we established the role of LiH in the decomposition of amine·alane adducts, and showed that the hydrogenation of Al* with NMPy and the decomposition of N-alkylpyrrolidine·alane adducts in the presence of LiH could be combined to generate donor-free LiAlH4.

The influence of water interfacial potentials on ion hydration in bulk water and near interfaces

The surface potential at the water liquid–vapor interface is discussed in relation to experimental determinations of bulk absolute ion hydration free energies. It is shown that, rather than the surface potential itself, the net electrostatic potential at the center of an uncharged solute can aid both in relating differences between tabulations of hydration free energies and in explaining differing classical and quantum surface potential estimates. Quantum mechanical results for the net potential are consistent with conclusions from previous classical simulations, suggesting a contribution from the net potential that can influence ion density profiles for single ions in water droplets.

A simplified confinement method for calculating absolute free energies and free energy and entropy differences.

A simple and robust formulation of the path-independent confinement method for the calculation of free energies is presented. The simplified confinement method (SCM) does not require matrix diagonalization or switching off the molecular force field, and has a simple convergence criterion. The method can be readily implemented in molecular dynamics programs with minimal or no code modifications. Because the confinement method is a special case of thermodynamic integration, it is trivially parallel over the integration variable. The accuracy of the method is demonstrated using a model diatomic molecule, for which exact results can be computed analytically. The method is then applied to the alanine dipeptide in vacuum, and to the α-helix ↔ β-sheet transition in a 16-residue peptide modeled in implicit solvent. The SCM requires less effort for the calculation of free energy differences than previous formulations because it does not require computing normal modes. The SCM has a diminished advantage for determining absolute free energy values, because it requires decreasing the MD integration step to obtain accurate results. An approximate confinement procedure is introduced, which can be used to estimate directly the configurational entropy difference between two macrostates, without the need for additional computation of the difference in the free energy or enthalpy. The approximation has convergence properties similar to those of the standard confinement method for the calculation of free energies. The use of the approximation requires about 5 times less wall-clock simulation time than that needed to compute enthalpy differences to similar precision from an MD trajectory. For the biomolecular systems considered in this study, the errors in the entropy approximation are under 10%. Practical applications of the methods to proteins are currently limited to implicit solvent simulations.

Assessing the quality of absolute hydration free energies among CHARMM-compatible ligand parameterization schemes.

Multipurpose atom-typer for CHARMM (MATCH), an atom-typing toolset for molecular mechanics force fields, was recently developed in our laboratory. Here, we assess the ability of MATCH-generated parameters and partial atomic charges to reproduce experimental absolute hydration free energies for a series of 457 small neutral molecules in GBMV2, Generalized Born with a smooth SWitching (GBSW), and fast analytical continuum treatment of solvation (FACTS) implicit solvent models. The quality of hydration free energies associated with small molecule parameters obtained from ParamChem, SwissParam, and Antechamber are compared. Given optimized surface tension coefficients for scaling the surface area term in the nonpolar contribution, these automated parameterization schemes with GBMV2 and GBSW demonstrate reasonable agreement with experimental hydration free energies (average unsigned errors of 0.9-1.5 kcal/mol and R(2) of 0.63-0.87). GBMV2 and GBSW consistently provide slightly more accurate estimates than FACTS, whereas Antechamber parameters yield marginally more accurate estimates than the current generation of MATCH, ParamChem, and SwissParam parameterization strategies. Modeling with MATCH libraries that are derived from different CHARMM topology and parameter files highlights the importance of having sufficient coverage of chemical space within the underlying databases of these automated schemes and the benefit of targeting specific functional groups for parameterization efforts to maximize both the breadth and the depth of the parameterized space.

Efficient methods for including quantum effects in Monte Carlo calculations of large systems: Extension of the displaced points path integral method and other effective potential methods to calculate properties and distributions

We present a procedure to calculate ensemble averages, thermodynamic derivatives, and coordinate distributions by effective classical potential methods. In particular, we consider the displaced-points path integral (DPPI) method, which yields exact quantal partition functions and ensemble averages for a harmonic potential and approximate quantal ones for general potentials, and we discuss the implementation of the new procedure in two Monte Carlo simulation codes, one that uses uncorrelated samples to calculate absolute free energies, and another that employs Metropolis sampling to calculate relative free energies. The results of the new DPPI method are compared to those from accurate path integral calculations as well as to results of two other effective classical potential schemes for the case of an isolated water molecule. In addition to the partition function, we consider the heat capacity and expectation values of the energy, the potential energy, the bond angle, and the OH distance. We also consider coordinate distributions. The DPPI scheme performs best among the three effective potential schemes considered and achieves very good accuracy for all of the properties considered. A key advantage of the effective potential schemes is that they display much lower statistical sampling variances than those for accurate path integral calculations. The method presented here shows great promise for including quantum effects in calculations on large systems.

Absolute Hydration Free Energies of Blocked Amino Acids: Implications for Protein Solvation and Stability

Most proteins perform their function in aqueous solution. The interactions with water determine the stability of proteins and the desolvation costs of ligand binding or membrane insertion. However, because of experimental restrictions, absolute solvation free energies of proteins or amino acids are not available. Instead, solvation free energies are estimated based on side chain analog data. This approach implies that the contributions to free energy differences are additive, and it has often been employed for estimating folding or binding free energies. However, it is not clear how much the additivity assumption affects the reliability of the resulting data. Here, we use molecular dynamics–based free energy simulations to calculate absolute hydration free energies for 15 N-acetyl-methylamide amino acids with neutral side chains. By comparing our results with solvation free energies for side chain analogs, we demonstrate that estimates of solvation free energies of full amino acids based on group-additive methods are systematically too negative and completely overestimate the hydrophobicity of glycine. The largest deviation of additive protocols using side chain analog data was 6.7 kcal/mol; on average, the deviation was 4 kcal/mol. We briefly discuss a simple way to alleviate the errors incurred by using side chain analog data and point out the implications of our findings for the field of biophysics and implicit solvent models. To support our results and conclusions, we calculate relative protein stabilities for selected point mutations, yielding a root-mean-square deviation from experimental results of 0.8 kcal/mol.

A Reparametrized Implicit Solvent Model for Accurate Computation of Hydration Free Energies

While solvation plays an important role in many chemical and biological processes, detailed solvent behavior is typically of much less interest than the effect of the solvent on the solute. Although explicit solvent treatment provides a very accurate description of the considered system, it is not necessary for many applications and can be replaced by implicit solvent models. A typical application is the computation of hydration free energies for small molecules. However a recent study [1] showed that there is still a gap between the accuracy of implicit models typically used in biomolecular simulations and explicit solvent treatment. To address this issue we have reparametrized an implicit solvent model consisting of a generalized Born term to model polar solvation and an extended nonpolar term that models cavity formation and Lennard-Jones interactions with water. When fitted to experimental hydration free energies of a large set of 499 small molecules, the model is able to reproduce hydration free energies with a similar error than those derived from explicit solvent computation, while still offering some degrees of freedom in the fit parameters. To test the transferability of the resulting model, we have applied it to the prediction of hydration free energies of Glycine-X-Glycine tri-peptides. This model will be part of the SIMONA [2] simulation package.[1] Knight, J. L. & Brooks III, C. L. Surveying implicit solvent models for estimating small molecule absolute hydration free energies. Journal of Computational Chemistry 32, 2909-2923 (2011).[2] Strunk, T. et al. SIMONA 1.0: An efficient and versatile framework for stochastic simulations of molecular and nanoscale systems. Journal of Computational Chemistry (2012).doi:10.1002/jcc.23089

Simulation study of ion pairing in concentrated aqueous salt solutions with a polarizable force field

The accuracy of empirical force fields is critical for meaningful molecular dynamics simulations of concentrated ionic solutions. Current models are typically developed on the basis of single ion properties such as the monohydrate energy in the gas phase, or the absolute hydration free energy at infinite dilution. However, the failure of these models to represent accurately the properties of concentrated solutions cannot be excluded. Here, these issues are illustrated for a polarizable potential based on classical Drude oscillators. To model accurately concentrated ionic solutions, the parameters of the potential functions are optimized to reproduce osmotic pressure data. The sodium-chloride potential of mean force in solution calculated from the empirically-adjusted model is consistent with the results from that calculated from ab initio CPMD simulations.