Conformation-Family Monte Carlo (CFMC): An efficient computational method for identifying the low-energy states of a macromolecule

Abstract

A highly efficient method, Conformation-Family Monte Carlo (CFMC), has been developed for searching the conformational space of a macromolecule and identifying its low-energy conformations. This method maintains a database of low-energy conformations that are clustered into families. The conformations in this database are improved iteratively by a Metropolis-type Monte Carlo procedure, together with energy minimization, in which the search is biased towards investigating the regions of the lowest-energy families. The CFMC method has the advantages of our earlier potential-smoothing methods (in that it 'coarse-grains' the conformational space and exploits information about nearby low-energy states), but avoids their disadvantages (such as the displacement of the global minimum at large smoothings). The CFMC method is applied to a test protein, domain B of Staphylococcal protein A. Independent CFMC runs yielded the same low-energy families of conformations from random starts, indicating that the thermodynamically relevant conformational space of this protein has been explored thoroughly. The CFMC method is highly efficient, performing as well as or better than competing methods, such as Monte Carlo with minimization, conformational-space annealing, and the self-consistent basin-to-deformed-basin method.