Combining a polarizable force-field and a coarse-grained polarizable solvent model: Application to long dynamics simulations of bovine pancreatic trypsin inhibitor (original) (raw)
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Journal of Computational Chemistry, 2011
The dynamic coupling between a polarizable protein force field and a particle-based implicit solvent model is described. The polarizable force field, TCPEp, developed recently to simulate protein systems, is characterized by a reduced number of polarizable sites, with a substantial gain in efficiency for an equal chemical accuracy. The Polarizable Pseudo-Particle (PPP) solvent model represents the macroscopic solvent polarization by induced dipoles placed on mobile Lennard-Jones pseudo-particles. The solvent-induced dipoles are sensitive to the solute electric field, but not to each other, so that the computational cost of solvent-solvent interactions is basically negligible. The solute and solvent induced dipoles are determined self-consistently and the equations of motion are solved using an efficient iterative multiple time step procedure. The solvation cost with respect to vacuum simulations is shown to decrease with solute size: the estimated multiplicative factor is 2.5 for a protein containing about 1000 atoms, and as low as 1.15 for 8000 atoms. The model is tested for six 20 ns molecular dynamics trajectories of a traditional benchmark system: the hydrated Bovine Pancreatic Trypsin Inhibitor (BPTI). Even though the TCPEp parameters have not been refined to be used with the solvent PPP model, we observe a good conservation of the BPTI structure along the trajectories. Moreover, our approach is able to provide a description of the protein solvation thermodynamic at the same accuracy as the standard Poisson-Boltzman continuum methods. It provides in addition a good description of the microscopic structural aspects concerning the solute/solvent interaction.
Solvation structure and dynamics of solutes in mixed polar solvents.
Molecular dynamics simulations of Na+ Cl− ion pairs in acetonitrile - dimethyl sulfoxide mixtures have been performed as a function of salt concentration and the composition of mixtures. Temperature dependence of the potential of mean force (PMF) is studied to assess the enthalpy and entropy contributions to the PMFs. Stability of contact ion pair increases with increase in temperature and decreases with the salt concentration. In higher salt concentrations, free energies of contact ion pair formation seem to approach a limiting value. Formation of the ion pairs is governed by the entropy irrespective of concentration of salt and mixture compositions.
A semi-implicit solvent model for the simulation of peptides and proteins
Journal of Computational Chemistry, 2004
We present a new model of biomolecules hydration based on macroscopic electrostatic theory, that can both describe the microscopic details of solvent-solute interactions and allow for an efficient evaluation of the electrostatic hydration free energy. This semi-implicit model considers the solvent as an ensemble of polarizable pseudoparticles whose induced dipole describe both the electronic and orientational solvent polarization. In the presented version of the model, there is no mutual dipolar interaction between the particles, and they only interact through short-ranged Lennard-Jones interactions. The model has been integrated into a molecular dynamics code, and offers the possibility to simulate efficiently the conformational evolution of biomolecules. It is able to provide estimations of the electrostatic solvation free energy within short time windows during the simulation. It has been applied to the study of two small peptides, the octaalanine and the N-terminal helix of ribonuclease A, and two proteins, the bovine pancreatic trypsin inhibitor and the B1 immunoglobin-binding domain of streptococcal protein G. Molecular dynamics simulations of these biomolecules, using a slightly modified Amber force field, provide stable and meaningful trajectories in overall agreement with experiments and all-atom simulations. Correlations with respect to Poisson-Boltzmann electrostatic solvation free energies are also presented to discuss the parameterization of the model and its consequences.
Journal of Chemical Theory and Computation, 2005
A polarizable force field, and associated continuum solvation model, have been developed for the explicit purpose of computing and studying the energetics and structural features of protein binding to the wide range of ligands with potential for medicinal applications. Parameters for the polarizable force field (PFF) are derived from gas-phase ab initio calculations and then utilized for applications in which the protein binding to ligands occurs in aqueous solvents, wherein the charge distributions of proteins and ligands can be dramatically altered. The continuum solvation model is based on a self-consistent reaction field description of solvation, incorporating an analytical gradient, that allows energy minimizations (and, potentially, molecular dynamics simulations) of protein/ligand systems in continuum solvent. This technology includes a nonpolar model describing the cost of cavity formation, and van der Waals interactions, between the continuum solvent and protein/ligand solutes. Tests of the structural accuracy and computational stability of the methodology, and timings for energy minimizations of proteins and protein/ligand systems in the condensed phase, are reported. In addition, the derivation of polarizability, electrostatic, exchange repulsion, and torsion parameters from ab initio data is described, along with the use of experimental solvation energies for determining parameters for the solvation model.
Journal of Computational Chemistry, 1995
The point-chart approximation of the Miertus-Scrocco-Tomasi solvation model (MST-PC) based on a continuum representation of the solvent has been incorporated in force field calculations. Application in molecular mechanics (MM) involves conformational equilibria in solution: rotational isomers of ethylene glycol (I), 1,2-difluoroethane (10, fluoroacetic acid (110, and representative conformers of macrocyclic receptors such as 18-crown-6 (IV), cryptand 2.2.2 (V), and t-butyl-calix[4]arenetetraamide (VI). Assessment of the MST-PC results is based on the comparison with ab initio reactive field calculations (for I-111), with the continuum model of Still (W. C. Still et al., J.
Ion solvation dynamics in an interaction-site model solvent
Chemical Physics, 1991
The molecular theory of the frequency-dependent and wavevectordependent longitudinal dielectric function eL( k, w) is derived for fluids comprising interaction-site model molecules in which point charges are located on the interaction sites. We find that cc( k, w) is a simple functional of a particular charge susceptibility X, O (k, o), which in turn is related to a collective chargecharge equilibrium time correlation function. The electrostatic part F &,.,,(t) of the time-dependent free energy of salvation of a solute that instantaneously changes its charge state is, on the other hand, determined by a charge susceptibility x$(k, k', w) of the solvent in the presence of the solute molecule in its initial charg state. Using an approximate relation between x$ and x,,,o we expnss FBom(t) in terms of x,,+. The restthing theory is applied to calculate the solvation time correlation function of the solute immersed in a dipolar hard sphere (DS) and in dipolar dumbbell (DD) model solvent; the mean spherical approximation and an extended mean spherical approximation are used to compute the structure of the DS and DD solvent models, respectively. With parameters chosen so that the two models have the same molecular volume and the same electric dipole moment, it is found that they have very nearly the same eL( k, o) except at large wavevector, but significantly different solvation time correlation ' Present address: