The protein folding problem remains one of the major unsolved challenges of structural biology. Although much has been learned experimentally concerning the later stages of folding, the initial collapse of the polypeptide chain to a compact state is still poorly understood. This is a critical step, since much of the search space is excluded at the point of collapse, and any algorithm which successfully folds a protein based on sequence information must be able to select those compact states which are most likely to form. The most important component of such a search is information concerning the interaction free energies of amino acid side chains, and for this, a set of pairwise interaction potentials is required.
Our approach to this problem is two-fold. Experimentally, we measure relative interaction free energies using affinity chromatography. We covalently bind functionality identical to a particular amino acid side chain to silica gel, and use this bonded phase as a stationary phase for liquid chromatography. Separation factors for amino acid derivatives in aqueous media on this support are then related to the relative free energies of interaction between the analytes and the bound side chain. We have established that aromatic-aromatic and aromatic-aliphatic interactions are qualitatively different than aliphatic-aliphatic interactions, both in magnitude and in the nature of their temperature dependence. Our work suggests that aromatic amino acid side chains play a critical role in the initiation of the collapse of the polypeptide chain, and are likely to also be important in mediating protein-protein and protein-substrate interactions. Besides experimental measurements, we also use lattice model Monte Carlo simulations to determine the minimal requirements of a potential for use in folding simulations. Our recent publications discuss the accuracy required for such a potential and test our theoretical predictions against a well-characterized lattice model for folding.