Theoretical Studies of Protein Folding

Cornell University, Ithaca NY

Investigators

Abstract

Sheraga, Harold A. MCB-0003722 The intellectual goal of this project is not, primarily, to predict protein structure but, rather, to gain an understanding of how inter-residue interactions determine the three-dimensional structure of a globular protein (the protein folding problem). For such an understanding, use is made of an ab initio approach, i.e. one based solely on the global optimization of a potential energy function (including the role of the solvent), without the use of secondary-structure predictions, homology modeling, threading, etc. Such an approach requires both a reliable potential function and an efficient procedure for global optimization; one cannot implement one without the other. Therefore, the specific aims are (i) to improve the potential function, (ii) to improve procedures for global optimization, and (iii) to apply them, first, to globular proteins of known structure and, then, to proteins of unknown structure in the CASP-like blind tests. The potential function is being improved by ab initio calculations plus refinement by the same global optimization procedure that was used for ab initio predictions of crystal structures (an analog of the protein folding problem). The multiple-minima problem (due to the existence of numerous local minima in the multidimensional potential energy surface) is being surmounted by a newly-developed hierarchical method, which incorporates (among other procedures) a united-residue (UNRES) description of the polypeptide chain, a Conformational Space Annealing (CSA) method, and the Monte-Carlo-plus-energy minimization (MCM) method and its descendant [the Conformation-Family Monte Carlo (CFMC) method]; this hierarchical method for global optimization was very successful in the CASP3 blind test, and is being significantly improved for later CASP-like blind tests. With the PI's own PC-Linux cluster, and considerable allocated time on both the NT clusters of the Cornell Theory Center and the supercomputer at the San Diego Supercomputer Center, sufficient access is available to the necessary resources to carry out this project. The proposed theoretical approach will provide a basic understanding of the conformational and folding properties of proteins, and will provide training, not only for the two research associates carrying out this research, but also for several postdocs and graduate students working together with these research associates.