Variational Method for Networkwide Analysis of Relative Ligand Binding Free Energies with Loop Closure and Experimental Constraints.

ABSTRACT: We describe an efficient method for the simultaneous solution of all free energies within a relative binding free-energy (RBFE) network with cycle closure and experimental/reference constraint conditions using Bennett Acceptance Ratio (BAR) and Multistate BAR (MBAR) analysis. Rather than solving the BAR or MBAR equations for each transformation independently, the simultaneous solution of all transformations are obtained by performing a constrained minimization of a global objective function. The nonlinear optimization of the objective function is subjected to affine linear constraints that couple the free energies between the network edges. The constraints are used to enforce the closure of thermodynamic cycles within the RBFE network, and to enforce an additional set of linear constraint

SUBMITTER: Giese TJ 

PROVIDER: S-EPMC8011336 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature