title: Free-energy calculations along a high-dimensional fragmented path with constrained dynamics.
abstract: Free-energy calculations for high-dimensional systems, such as peptides or proteins, always suffer from a serious sampling problem in a huge conformational space. For such systems, path-based free-energy methods, such as thermodynamic integration or free-energy perturbation, are good choices. However, both of them need sufficient sampling along a predefined transition path, which can only be controlled using restrained or constrained dynamics. Constrained simulations produce more reasonable free-energy profiles than restrained simulations. But calculations of standard constrained dynamics require an explicit expression of reaction coordinates as a function of Cartesian coordinates of all related atoms, which may be difficult to find for the complex transition of biomolecules. In this paper, we propose a practical solution: (1) We use restrained dynamics to define an optimized transition path, divide it into small fragments, and define a virtual reaction coordinate to denote a position along the path. (2) We use constrained dynamics to perform a formal free-energy calculation for each fragment and collect the values together to provide the entire free-energy profile. This method avoids the requirement to explicitly define reaction coordinates in Cartesian coordinates and provides a novel strategy to perform free-energy calculations for biomolecules along any complex transition path.
authors.affiliation: Biomolecular Physics and Modeling Group, Department of Physics, Huazhong University of Science and Technology Wuhan 430074, Hubei, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Chen
authors.forename: Yanzhao
authors.initials: Y
authors.lastname: Huang
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiao
mesh_terms: D004151:Dipeptides / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D004151:Dipeptides; D012997:Solvents