Solvation Structure and Quasidynamics of Biomolecules Steered with Effective Solvation Forces Obtained From Molecular Theory of Solvation

Abstract

Three-dimensional reference interaction site model with Kovalenko-Hirata closure (3D-RISM-KH molecular theory of solvation) is Ornstein-Zernike type integral equation theory of liquids. Based on first principles of statistical mechanics, 3D-RISM-KH consistently accounts for effect of chemical specificities of solvent, co-solvent, ions, and ligands on biomolecules solvation structure and thermodynamics, including steric forces, hydrophobicity, hydrogen bonding, and other effective interactions. 3D-RISM-KH supplemented with the partial molar volume correction, a.k.a. “Universal Correction” (UC), provides an excellent agreement with experimental data on a large set of small compounds for solvation free energies in octanol and water, and octanol-water partition coefficients. 3D-RISM-KH structural water detection and placement are implemented in Amber Tools and Molecular Operating Environment (MOE) packages. Structural water plays critical role in protein interactions and functions; case studies include HET-s prion, Aβ oligomer and fibril formation, folding promotion in GroEL chaperonin, and ligand binding to maltose-binding protein. Multi-time-step MD of biomolecules steered with mean solvation forces obtained from 3D-RISM-KH at outer steps and treated with generalized solvation force extrapolation (GSFE) at inner steps is efficiently stabilized with the optimized isokinetic Nose-Hoover chain (OIN) thermostat. The accuracy of GSFE and efficiency of OIN allow picoseconds outer steps while accurately reproducing conformational properties, as validated on hydrated alanine dipeptide, miniprotein 1L2Y, and protein G. Due to 3D-RISM-KH statistical averaging over rare events of solvent exchange and localization in biomolecular spaces, this quasidynamics results in time scale compression of protein conformational changes coupled with solvent and so in huge acceleration of conformational sampling. This provides up to 1000-fold effective speedup of sampling, compared to conventional MD with explicit solvent, and enables to fold the miniprotein from a fully denatured state in 60ns quasidynamics, cf. 4-9μs folding time in experiment.