Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 62, Issue 11, Pages 2846-2856Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.1c01532
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Funding
- HPCI System Research Project [hp160207, hp170254, hp180201, hp190181, hp200129, hp200135, hp210172, hp210177]
- MEXT/JSPS KAKENHI [19H05645, 20K06582]
- RIKEN pioneering project in Biology of Intracellular Environment
- MEXT Program for Promoting Research on the Supercomputer Fugaku (Biomolecular dynamics in a living cell/MD-driven Precision Medicine)
- RIKEN pioneering project in Dynamic Structural Biology
- RIKEN pioneering project in Glycolipidlogue
- Grants-in-Aid for Scientific Research [20K06582, 19H05645] Funding Source: KAKEN
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The free-energy perturbation (FEP) method is an essential tool in in silico drug design, used to predict the free-energy changes of biomolecules in solvation and binding. However, conventional FEP requires computationally expensive reciprocal-space calculations. To address this limitation, this study proposes a modified Hamiltonian approach that introduces nonuniform scaling into the electrostatic potential, improving computational performance and avoiding the need for additional reciprocal-space calculations.
The free-energy perturbation (FEP) method predicts relative and absolute free-energy changes of biomolecules in solvation and binding with other molecules. FEP is, therefore, one of the most essential tools in in silico drug design. In conventional FEP, to smoothly connect two thermodynamic states, the potential energy is modified as a linear combination of the end-state potential energies by introducing scaling factors. When the particle mesh Ewald is used for electrostatic calculations, conventional FEP requires two reciprocal-space calculations per time step, which largely decreases the computational performance. To overcome this problem, we propose a new FEP scheme by introducing a modified Hamiltonian instead of interpolation of the end-state potential energies. The scheme introduces nonuniform scaling into the electrostatic potential as used in Replica Exchange with Solute Tempering 2 (REST2) and does not require additional reciprocal-space calculations. We tested this modified Hamiltonian in FEP calculations in several biomolecular systems. In all cases, the calculated free-energy changes with the current scheme are in good agreement with those from conventional FEP. The modified Hamiltonian in FEP greatly improves the computational performance, which is particularly marked for large biomolecular systems whose reciprocal-space calculations are the major bottleneck of total computational time.
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