Cycle Closure Estimation of Relative Binding Affinities and Errors

摘要

Methods for assessing the consistency and reliability of the calculations using cycle closures in relative binding free energy calculation paths. The methods are used for determining relative strength of binding between a receptor and individual members of a set ligands to form complexes between individual ligand set members and the receptor, in which the binding free energy difference with the lowest error is determined by probabilistic determination of the free energy differences and error distributions about those differences along each of the legs of the closed thermodynamic cycle that probabilistically lead to the hysteresis(es) value(s) observed for each closed of the closed thermodynamic cycle.

主权项

1. A computer-implemented method of determining relative strength of binding between a receptor and individual members of a set ligands to form complexes between individual ligand set members and the receptor, the method comprising a computer-implemented determination of multiple relative binding free energy differences for a set of ligand pairs forming at least one closed cycle, and a computer implemented determination of hysteresis magnitude about each closed thermodynamic cycle, comprising:
a. a computer implemented probabilistic determination of the free energy differences and error distributions about those free energy differences along each of the legs of the closed thermodynamic cycle that probabilistically lead to the hysteresis value observed for the closed thermodynamic cycles; b. a computer implemented determination of the most probable free energy difference for each leg in the closed thermodynamic cycle included in the probabilistic model determined in a; c. a computer implemented determination of the most probable error associated with the most probable binding free energy difference for each pair of ligands along each leg in the closed thermodynamic cycle from the probabilistic determination in b.; d. a computer implemented output of values representing the relative binding free energies and errors in c. to a computer user.