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Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering
Xiaorong Liu1, Charles L Brooks Iii1,2
1Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
Journal of Chemical Theory and Computation
|January 17, 2024
Summary
Enhanced sampling techniques like replica exchange with charge tempering (REChgT) significantly improve free energy calculations for proteins with buried charges. This method accelerates convergence, providing crucial molecular insights for complex biological systems.
Area of Science:
- Biophysics
- Computational Chemistry
- Structural Biology
Background:
- Buried ionizable groups in proteins are critical for structure and function.
- Experimental methods alone face challenges in elucidating detailed molecular mechanisms.
- Atomistic simulations offer high-resolution insights but often suffer from insufficient sampling.
Purpose of the Study:
- To introduce and validate a novel enhanced sampling technique, replica exchange with charge tempering (REChgT).
- To combine REChgT with multisite λ dynamics (MSλD) for improved free energy calculations.
- To investigate systems with buried charges, including pKa prediction and relative stability.
Main Methods:
- Development and application of replica exchange with charge tempering (REChgT).
- Integration of REChgT with multisite λ dynamics (MSλD) for enhanced sampling.
- Atomistic simulations of two distinct systems containing buried charges.
Main Results:
- REChgT dramatically increased sampling in both conformational and alchemical spaces.
- Significant reduction in computational time required for free energy convergence.
- Successful application to pKa prediction and buried charge pair stability.
Conclusions:
- REChgT is an effective enhanced sampling technique for systems with buried charges.
- The combination of REChgT and MSλD accelerates free energy calculations.
- Sufficient sampling is crucial for developing accurate free energy methods in computational biophysics.
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