We have developed multi-time-step molecular dynamics of biomolecules steered with mean solvation forces obtained from the three-dimensional reference interaction site model (3D-RISM) complemented with the Kovalenko-Hirata (KH) closure.1 The 3D-RISM-KH molecular theory of solvation2 yields solvation structure in terms of 3D maps of correlation functions of solvent interaction sites around a solute (supra)molecule and solvation thermodynamics at once analytically. It consistently accounts for effects of chemical specificities of solvent, co-solvent, ions, and ligands in a wide range of space and time scales (problematic for molecular simulation and not adequately captured with empirically constructed continuum solvation models), including solvent exchange, structural solvent, desolvation, hydrophobicity, hydrogen bonding, and other effective interactions. We calculate mean solvation forces acting on biomolecule atoms at inner time steps of MD by generalized solvation force extrapolation (GSFE) based on those in conformations with closest atomic coordinates at outer time steps obtained by converging the 3D-RISM-KH integral equations. GSFE includes non-Eckart like transformation of coordinate space separately for each solute atom, extension of the force-coordinate basis set followed by selection of the best subset, balancing the normal equations to minimize deviations by modified least squares, and incremental increase of outer time step in motion integration. Biomolecule evolution is stabilized with the optimized isokinetic Nosé-Hoover chain (OIN) thermostat. We validated the hybrid OIN/GSFE/3D-RISM-KH integrator on asphaltene dimer in toluene solvent, and alanine dipeptide, miniprotein 1L2Y, and protein G in water.1b The GSFE accuracy and OIN efficiency allow huge outer steps of 1–4 ps while accurately reproducing conformational properties. Quasidynamics steered with 3D-RISM-KH mean solvation forces gives time scale compression of protein conformational changes and achieves up to 1000–fold effective sampling speedup with respect to real time dynamics or conventional MD with explicit solvent. This enabled us to fold the miniprotein from a fully denatured state in 60ns quasidynamics, compared to 4–9 µs physical folding time in experiment. (1) (a) J.Chem.Phys. 2013,139,244106. (b) J.Chem.Theory Comput. 2015,11,1875. (2) (a) Molecular Theory of Solvation. Hirata, F. (ed.) Kluwer, Dordrecht, 2003. (b) J.Chem.Phys. 1999,110,10095. (c) Pure Appl.Chem. 2013,85,159.

Quasidynamics of biomolecules steered with 3D-RISM-KH mean solvation forces

251st National Meeting (2016)

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