The physics and bioinformatics of binding and folding-an energy landscape perspective.

It has been recognized in the last few years that unstructured proteins play an important role in biological organisms, often participating in signal transduction, transcriptional regulation, and a variety of other regulatory activities. Various hypotheses have been put forward for the ubiquity of the unfolded state; rapid turnover, faster or more specific binding kinetics, multifunctionality may all possibly explain apparent ubiquitousness of unfolded proteins in eukaryotic cells. In this paper we extend the energy landscape theory of protein folding to construct an analytical model of how binding and folding are coupled thermodynamically when the energy landscape is partially rugged. To deduce the parameters that enter the theory, which is based on Generalized Random Energy Model, we have analyzed in a bioinformatic sense a large structural database of more than 500 protein complexes. We find that Miyazawa-Jernigan contact potential shows similar energy gaps for folding for both hydrophobic and hydrophilic proteins, but that for binding contacts hydrophobic interfaces turn out to be funneled while hydrophilic ones are antifunneled. This suggests evolution has found a mechanism for avoiding frustration between folding and binding by making use of indirect water-mediated interactions. By juxtaposing the monomeric protein folding free energy profile in the protein complex database with another database consisting of only well-folded monomers, we estimate that at least 15% of monomers in the former database are unfolded in the absence of partner protein interface interactions. When employing the parameters characteristic of these unfolded monomers to construct binding/folding phase diagrams, we find that these monomers would indeed fold if sufficiently stabilizing binding contacts, consistent with that fold, are formed. Copyright 2003 Wiley Periodicals, Inc. Biopolymers: 333-349, 2003