Simulated Solute Tempering 2: An Efficient and Practical Approach to Protein Conformational Sampling and Binding Events

Molecular dynamics (MD) simulations are powerful tools for studying the movement and interactions of molecules, but they can be computationally expensive, especially for large biomolecules like proteins. This is problematic because accurately simulating the motions of these molecules is key to understanding their function. Enhanced sampling methods, such as Simulated Tempering (ST), temperature Replica Exchange Molecular Dynamics (REMD) and Replica Exchange with Solute Tempering (REST and REST2), have been developed to overcome this challenge by improving the efficiency of MD simulations. This article presents a new enhanced sampling method called Simulated Solute Tempering 2 (SST2) that builds upon the strengths of ST and REST2. SST2 selectively scales the interactions inside a biomolecule and with its surrounding environment, effectively accelerating the exploration of its different structural states and their stability at various temperatures. SST2 was tested on three different systems (chignolin CLN025, Trp-Cage, and a protein-peptide complex, p97/PNGase) and found to achieve comparable or superior sampling efficiency to ST, SST1 and REST2 while requiring fewer temperature rungs. Notably, SST2 is particularly well-suited for investigating large biomolecular systems, making it a valuable tool for studying a wide range of biomolecular processes, from protein folding to ligand binding. Significance StatementAccurately simulating the motions of biological molecules like proteins is key to understanding their function. However, this is computationally expensive, especially for large systems or slow processes. To overcome this, we developed Simulated Solute Tempering 2 (SST2), a novel algorithm that improves the efficiency of molecular dynamics (MD) simulations. SST2 selectively scales the interactions inside a biomolecule and with its surrounding environment, accelerating the exploration of its different structures and their stability at various temperatures. This allows SST2 to achieve remarkable performances with a clear improved ease of use compare to similar methods, particularly for large systems like protein-ligand complexes. This makes SST2 a valuable tool for studying a wide range of biomolecular processes, from protein folding to ligand binding. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/613476v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@761755org.highwire.dtl.DTLVardef@f5df1forg.highwire.dtl.DTLVardef@ba93dorg.highwire.dtl.DTLVardef@193e7eb_HPS_FORMAT_FIGEXP M_FIG C_FIG