Biomolecular Simulations with the Three-Dimensional Reference Interaction Site Model with the Kovalenko-Hirata...

Area of Science:

• Computational chemistry
• Molecular modeling
• Statistical mechanics

Background:

• The 3-dimensional reference interaction site model with Kovalenko-Hirata closure (3D-RISM-KH) is a key statistical mechanics theory for molecular solvation.
• It has been successfully applied to diverse systems, from small molecules to polymers and macromolecules.
• 3D-RISM-KH explains molecular mechanisms in protein self-assembly, aggregation, and protein-ligand binding.

Purpose of the Study:

• To develop and implement a multiscale modeling framework combining 3D-RISM-KH with advanced molecular dynamics (MD).
• To enhance computational efficiency for biomolecular simulations while maintaining accuracy in calculating equilibrium properties.
• To demonstrate the utility of the new algorithm for various biomolecular systems and applications.

Main Methods:

• Coupling 3D-RISM-KH with a novel multiple time-step MD protocol using a Nosé-Hoover chain thermostat.
• Utilizing generalized solvation force extrapolation (GSFE) to drive the dynamics with solvation forces from 3D-RISM-KH.
• Implementing the multiscale OIN/GSFE/3D-RISM-KH algorithm in the Amber package for biomolecular simulations.

Main Results:

• Achieved gigantic outer time-steps up to picoseconds, enabling accurate equilibrium property calculations.
• Demonstrated a solvent sampling rate approximately 150 times faster than standard MD simulations in explicit water.
• Successfully modeled alanine dipeptide, miniprotein 1L2Y, and protein G in aqueous solution.

Conclusions:

• The multiscale OIN/GSFE/3D-RISM-KH algorithm significantly accelerates biomolecular simulations.
• This enhanced technique is effective for calculating protein-ligand binding energies, predicting binding sites, and determining molecular solvation energies.
• Further computational speed-up is possible by optimizing solvation layer considerations and closure relations.