Enhanced Sampling in Free Energy Calculations: Combining XXXX with the Bennett's Acceptance Ratio and Enveloping Distribution Sampling Methods.

@entity6128 @entity3929 @entity14062 @entity563
One of the key requirements for the accurate calculation of free energy differences is proper sampling of conformational space. Especially in biological applications, molecular dynamics simulations are often confronted with rugged energy surfaces and high energy barriers, leading to insufficient sampling and, in turn, poor convergence of the free energy results. In this work, we address this problem by employing enhanced sampling methods. We explore the possibility of using @entity14062 ( @entity14062 ) to speed up the exploration process in free energy simulations. To obtain improved free energy differences from such simulations, it is necessary to account for the effects of the bias due to the guiding forces. We demonstrate how this can be accomplished for the Bennett's acceptance ratio (BAR) and the @entity6128 ( @entity6128 ) methods. While BAR is considered among the most efficient methods available for free energy calculations, the @entity6128 method developed by Christ and van Gunsteren is a promising development that reduces the computational costs of free energy calculations by simulating a single reference state. To evaluate the accuracy of both approaches in connection with enhanced sampling, @entity6128 was implemented in CHARMM. For testing, we employ benchmark systems with analytical reference results and the mutation of @entity3929 to @entity563 . We find that @entity14062 with reweighting can provide accurate results for BAR and @entity6128 where conventional molecular dynamics simulations fail. In addition, we compare the performance of @entity6128 with other free energy methods. We briefly discuss the implications of our results and provide practical guidelines for conducting free energy simulations with @entity14062 .
