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Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering.

ABSTRACT: Buried ionizable groups in proteins often play important structural and functional roles. However, it is generally challenging to study the detailed molecular mechanisms solely based on experimental measurements. Free energy calculations using atomistic simulations, on the other hand, complement experimental studies and can provide high temporal and spatial resolution information that can lead to mechanistic insights. Nevertheless, it is also well recognized that sufficient sampling of such atomistic simulations can be challenging, considering that structural changes related to the buried charges may be very slow. In the present study, we describe a simple but effective enhanced sampling technique called replica exchange with charge tempering (REChgT) with a novel free energy method, multisite λ dynamics (MSλD), to study two systems containing buried charges, pK_a prediction of a small molecule, orotate, in complex with the dihydroorotate dehydrogenase, and relative stability of a Glu-Lys pair buried in the hydrophobic core of two variants of Staphylococcal nuclease. Compared to the original MSλD simulations, the usage of REChgT dramatically increases sampling in both conformational and alchemical spaces, which directly translates into a significant reduction of wall time to converge the free energy calculations. This study highlights the importance of sufficient sampling toward developing improved free energy methods.

SUBMITTER: Liu X

PROVIDER: S-EPMC11275198 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering.

Liu Xiaorong X Brooks Iii Charles L CL

Journal of chemical theory and computation 20240117 3

Buried ionizable groups in proteins often play important structural and functional roles. However, it is generally challenging to study the detailed molecular mechanisms solely based on experimental measurements. Free energy calculations using atomistic simulations, on the other hand, complement experimental studies and can provide high temporal and spatial resolution information that can lead to mechanistic insights. Nevertheless, it is also well recognized that sufficient sampling of such atom ...[more]

PMID: 38232295

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Project description:Replica exchange with solute tempering (REST) is a highly effective variant of replica exchange for enhanced sampling in explicit solvent simulations of biomolecules. By scaling the Hamiltonian for a selected "solute" region of the system, REST effectively applies tempering only to the degrees of freedom of interest but not the rest of the system ("solvent"), allowing fewer replicas for covering the same temperature range. A key consideration of REST is how the solute-solvent interactions are scaled together with the solute-solute interactions. Here, we critically evaluate the performance of the latest REST2 protocol for sampling large-scale conformation fluctuations of intrinsically disordered proteins (IDPs). The results show that REST2 promotes artificial protein conformational collapse at high effective temperatures, which seems to be a designed feature originally to promote the sampling of reversible folding of small proteins. The collapse is particularly severe with larger IDPs, leading to replica segregation in the effective temperature space and hindering effective sampling of large-scale conformational changes. We propose that the scaling of the solute-solvent interactions can be treated as free parameters in REST, which can be tuned to control the solute conformational properties (e.g., chain expansion) at different effective temperatures and achieve more effective sampling. To this end, we derive a new REST3 protocol, where the strengths of the solute-solvent van der Waals interactions are recalibrated to reproduce the levels of protein chain expansion at high effective temperatures. The efficiency of REST3 is examined using two IDPs with nontrivial local and long-range structural features, including the p53 N-terminal domain and the kinase inducible transactivation domain of transcription factor CREB. The results suggest that REST3 leads to a much more efficient temperature random walk and improved sampling efficiency, which also further reduces the number of replicas required. Nonetheless, our analysis also reveals significant challenges of relying on tempering alone for sampling large-scale conformational fluctuations of disordered proteins. It is likely that more efficient sampling protocols will require incorporating more sophisticated Hamiltonian replica exchange schemes in addition to tempering.

Dataset Information

Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering.

Publications

Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering.

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