Random walk in orthogonal space to achieve efficient free-energy simulation of complex systems.
In the past few decades, many ingenious efforts have been made in the development of free-energy simulation methods. Because complex systems often undergo nontrivial structural transition during state switching, achieving efficient free-energy calculation can be challenging. As identified earlier, the "Hamiltonian" lagging, which reveals the fact that necessary structural relaxation falls behind the order parameter move, has been a primary problem for generally low free-energy simulation efficiency. Here, we propose an algorithm by achieving a random walk in both the order parameter space and its generalized force space; thereby, the order parameter move and the required conformational relaxation can be efficiently synchronized. As demonstrated in both the alchemical transition and the conformational transition, a leapfrog improvement in free-energy simulation efficiency can be obtained; for instance, (i) it allows us to solve a notoriously challenging problem: accurately predicting the pK(a) value of a buried titratable residue, Asp-66, in the interior of the V66E staphylococcal nuclease mutant, and (ii) it allows us to gain superior efficiency over the metadynamics algorithm.
Zheng
Lianqing
L
Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.
Chen
Mengen
M
Yang
Wei
W
D003198:Computer Simulation; D004058:Diffusion; D006863:Hydrogen-Ion Concentration; D008722:Methods; D008836:Micrococcal Nuclease / Q000737:chemistry / Q000235:genetics; D008956:Models, Chemical; D011487:Protein Conformation; D013816:Thermodynamics
D008836:Micrococcal Nuclease