Combinatorial approaches to protein stability and structure.

Why do proteins adopt the conformations that they do, and what determines their stabilities? While we have come to some understanding of the forces that underlie protein architecture, a precise, predictive, physicochemical explanation is still elusive. Two obstacles to addressing these questions are the unfathomable vastness of protein sequence space, and the difficulty in making direct physical measurements on large numbers of protein variants. Here, we review combinatorial methods that have been applied to problems in protein biophysics over the last 15 years. The effects of hydrophobic core composition, the most important determinant of structure and stability, are still poorly understood. Particular attention is given to core composition as addressed by library methods. Increasingly useful screens and selections, in combination with modern high-throughput approaches borrowed from genomics and proteomics efforts, are making the empirical, statistical correlation between sequence and structure a tractable problem for the coming years.