Ab initio methods.

Abstract

Ab initio structure prediction seeks to predict the native conformation of a protein from the amino acid sequence alone. Such attempts are both a fundamental test of our understanding of protein folding, and an important practical challenge in this era of large scale genome sequencing projects, which are producing large numbers of protein sequences for which no three-dimensional structural information is available. Anfinsen showed forty years ago that all of the information necessary for a protein to fold to the native state resides in the protein’s amino acid sequence (Anfinsen et al., 1961; Anfinsen, 1973). In the absence of large kinetic barriers in the free energy landscape, Anfinsen’s results and those of large numbers of researchers in the intervening years suggest that the native conformations of most proteins are the lowest free energy conformations for their sequences (for a description of some notable exceptions, see Baker and Agard, 1994). Successful structure prediction requires a free energy function sufficiently close to the true potential for the native state to be at one of the lowest free energy minima, as well as a method for searching conformational space for low energy minima. Ab initio structure prediction is challenging because current potential functions have limited accuracy, and the conformational space to be searched is vast. Many methods use reduced representations, simplified potentials, and coarse search strategies in recognition of this resolution limit (Simons et al., 1997; Samudrala et al., 1999; Ortiz et al., 1999; Pillardy et al., 2001). Encouragingly, these simplified methods are starting to show some success in protein structure prediction (Murzin, 2001; Lesk, Lo Conte, and Hubbard, 2001) and have advanced to the point where genome scale modeling may become useful.