Biasing Potential Replica Exchange Multisite lambda-Dynamics for Efficient Free Energy Calculations

摘要

Traditional free energy calculation methods are Well-known for their drawbacks in scalability and speed in converging results particularly for calculations with large perturbations. In the present work, we report on the development of biasing potential replica exchange multisite 2-dynamics (BP-REX MS lambda D), which is a free energy method that is capable Of performing simultaneous alchemical free energy transformations, including perturbations between flexible Moieties. BP-REX MS lambda D and the original MS lambda D are applied to a series of symmetrical 2,5-benzoquinone derivatives covering a diverse chemical space and range of conformational flexibility. Improved A-space sampling is observed for the BP-REX MS lambda D simulations, yielding a 2-5-fold increase in the number of transitions between substituents compared to traditional MS lambda D. We also demonstrate the efficacy of varying the value of c, the parameter that controls the ruggedness of the landscape mediating the sampling of lambda-states, based on the flexibility of the fragment. Finally, we developed a protocol for maximizing the transition frequency between fragments. This protocol reduces the "kinetic barrier" for alchemically transforming fragments by grouping and ordering based on volume. These findings are applied to a challenging test set involving a series of geldanamycin-based inhibitors of heat shock protein 90 (Hsp90). Even though the perturbations span volume changes by as large as 60 angstrom(3), the values for the free energy Change achieve an average unsigned error (AUE) of 1.5 kcal/mol relative to experimental K-d measurements with a reasonable correlation (R = 0.56) Our results suggest that the BP-REX MS lambda D algorithm is a highly efficient and scalable free energy method, which when utilized Will enable routine calculations On the order of hundreds of compounds using only a few simulations.