Virtual substitution scan via single-step free energy perturbation

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Molecular dynamics (MD) simulations are increasingly common, generating long trajectories.
• Most MD trajectories are from plain simulations, not utilizing enhanced sampling methods.
• There is a need to leverage existing MD data for further analysis.

Purpose of the Study:

• To develop a toolkit for post-processing plain MD trajectories.
• To enable fast free energy scans of aryl hydrogen substitutions with small functional groups.
• To promote the reuse of existing MD simulation data.

Main Methods:

• Developed the Virtual Substitution Scan (VSS) toolkit as a VMD plugin.
• Utilized the single-step free energy perturbation (sFEP) method.
• Explicitly sampled functional group dihedrals for improved accuracy and performance.

Main Results:

• VSS successfully computed solvation free energy changes for benzene substituted with 12 functional groups.
• VSS calculated relative binding free energies for T4 lysozyme ligands.
• VSS results showed good agreement with multi-step free energy perturbation (mFEP) calculations.
• VSS demonstrated significantly lower computational cost than mFEP.

Conclusions:

• VSS is an effective tool for rapid free energy scanning of small functional group substitutions.
• The toolkit enables efficient analysis of existing molecular dynamics trajectories.
• VSS offers a promising approach for lead optimization in drug discovery.