the energy computation paradox and ab initio protein folding能量蛋白质折叠计算矛盾和从头开始.pdfVIP

The Energy Computation Paradox and ab initio Protein Folding 1 1 1 1 1 2 John C. Faver , Mark L. Benson , Xiao He , Benjamin P. Roberts , Bing Wang , Michael S. Marshall , 2 1 C. David Sherrill , Kenneth M. Merz Jr. * 1 Quantum Theory Project, University of Florida, Gainesville, Florida, United States of America, 2 Center for Computational Molecular Science and Technology, School of Chemistry and Biochemistry, and School of Computational Science and Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America Abstract The routine prediction of three-dimensional protein structure from sequence remains a challenge in computational biochemistry. It has been intuited that calculated energies from physics-based scoring functions are able to distinguish native from nonnative folds based on previous performance with small proteins and that conformational sampling is the fundamental bottleneck to successful folding. We demonstrate that as protein size increases, errors in the computed energies become a significant problem. We show, by using error probability density functions, that physics-based scores contain significant systematic and random errors relative to accurate reference energies. These errors propagate throughout an entire protein and distort its energy landscape to such an extent that modern scoring functions should have little chance of success in finding the free energy minima of large proteins. Nonetheless, by understanding errors in physics-based score functions, they can be reduced in a post-hoc manner, improving accuracy in energy computation and fol