EXPRORER: Rational Cosolvent Set Construction Method for Cosolvent Molecular Dynamics Using Large-Scale Computation

Abstract

Cosolvent molecular dynamics (CMD) simulations involve an MD simulation of a protein in the presence of explicit water molecules mixed with cosolvent molecules to perform hotspot detection, binding site identification, and binding energy estimation, while other existing methods (e.g., MixMD, SILCS, and MDmix) utilize small molecules that represent functional groups of compounds. However, the cosolvent selections employed in these methods differ and there are only a few cosolvents that are commonly used in these methods. In this study, we proposed a systematic method for constructing a set of cosolvents for drug discovery, termed the EXtended PRObes set construction by REpresentative Retrieval (EXPRORER). First, we extracted typical substructures from FDA-approved drugs, generated 138 cosolvent structures, and for each cosolvent molecule, we conducted CMD simulations to generate a spatial probability distribution map of cosolvent atoms (PMAP). Analyses of PMAP similarity revealed that a cosolvent pair with a PMAP similarity greater than 0.70−0.75 shared similar structural features. We present a method for the construction of a cosolvent subset that satisfies a similarity threshold for all cosolvents, and we tested the constructed sets for four proteins. To our knowledge, this is the first study to include a systematic proposal for cosolvent set construction, and thus, the EXPRORER cosolvents will provide deeper insights into ligand binding sites of various proteins.

Extracting Atomic Contributions to Binding Free Energy Using Molecular Dynamics Simulations with Mixed Solvents (MDmix)

“…An alternative approach to ensure transferability is to simulate a very large set of solvent probes, each representing a chemical moiety present in typical drugs. This was recently demonstrated by Yanagisawa and co-workers using a set of 138 cosolvents [ 32 ]. Simulation of a much smaller set of cosolvents containing the essential atom types, followed by atomic partitioning of ΔG bind, is far more efficient [ 33 , 34 ].…”

AAp-MSMD: Amino Acid Preference Mapping on Protein–Protein Interaction Surfaces Using Mixed-Solvent Molecular Dynamics

“…After probe preparation, MSMD was performed following the protocol referring to EXPRORER . Notably, the initial positions of the probes affect the results, particularly in short MD simulations, and this initial position dependence influences the convergence of the analysis results.…”

“…Asparagine and glutamine residue flips were also handled appropriately. Subsequently, the preprocessed proteins were used as the input structure for the simulation . For hotspot detection, AAp-MSMD was performed for each target protein–amino acid probe pair, and each max-PMAP was qualitatively compared to each residue position in the peptide.…”

“…After probe preparation, MSMD was performed following the protocol referring to EXPRORER. 35 Notably, the initial positions of the probes affect the results, particularly in short MD simulations, and this initial position dependence influences the convergence of the analysis results. Therefore, the following protocols were independently performed 40 times with different initial probe coordinates to achieve efficient sampling.…”

Divide and Conquer. Pocket-Opening Mixed-Solvent Simulations in the Perspective of Docking Virtual Screening Applications for Drug Discovery

“…Indeed, this alternative mapping strategy might be able to unveil cryptic sites that would simply never be discovered by conventional approaches. Different approaches to mixed-solvent MD simulations have been developed and include MixMD, , MDMix, SILCS, , CAT, and others. − One of the main caveats of previous studies is that they tend to run short simulations (10–50 ns) which are often too short to observe larger conformational changes and/or identify buried pockets. Schmidt et al showed how pockets in their study tend to open after the 100 ns mark.…”