Optimization of parameters in macromolecular potential energy functions byconformational space annealing

A general protocol for refining the parameters of macromolecular potential energy functions by optimizing criteria that compare nativelike and normati ve conformations of one or more benchmark protein(s) is described. The prot ocol exploits the high efficiency of conformational space annealing (CSA) i n finding the lowest-energy conformation of an isolated macromolecule. A no vel form of the CSA method, local CSA, is introduced to provide better samp ling of nativelike conformations. The computational expense of the protocol is reduced significantly by a linear approximation that estimates the ener gy of the (reminimized) native and normative conformations after every chan ge of the force field parameters. The protocol is illustrated by optimizing the parameters of two force fields used in the CASP3 and CASP4 experiments , respectively. Another version of this general protocol (with different op timization criteria and optimization methods) was used to determine the par ameters for the alpha, beta and alpha/beta force fields used in the CASP4 e xperiment, as reported in a companion publication.