Theory of protein structure.

    There are two theoretical approaches to the protein folding problem.  The first approach is to consider proteins merely as long polymer chains whose energies must be minimized by searching in the space of torsion angles or by using simplified lattice models.  An alternative way of looking at the problem is to consider proteins as systems of regular secondary structures.   In terms of secondary structure, the protein folding process can be represented as a sequence of the following events: (1) formation of a -helices and b -sheets by the hydrophobically collapsed peptide chain, (2) assembly of the regular secondary structure elements into the protein core, and (3) joining of nonregular loops and the less stable "peripheral" helices and b -strands to the core and the association of independently formed domains.  A theory of protein self-organization must reproduce all these events to finally calculate three-dimensional structures of proteins.  The development of this theory requires, first of all, a design  of new, specialized force field to calculate free energies of a-helices and b-sheets relative to the coil (the secondary structures and the coil are represented by large ensembles of conformers) , instead of enthalpies of individual conformers given by molecular mechanics force fields.  This theory requires also a design of alternative global energy optimization strategies, such as calculation of the lowest energy partition of the peptide chain into different secondary and supersecondary structures, instead of searching in the space of torsion angles or lattice simulations. 

    In a recent paper (Biopolymers, 42:239-269), we describe how the "secondary structure force field" can be developed for a -helical peptides and proteins by combining experimental a -helix stability data, accessible surface estimations, and some adjustable parameters (the entropy and enthalpy of helix-coil transition, the transfer energy of helix backbone and side-chains, parameters of the bound coil and others) that can be compared with independent experimental measurements.  The found parametrization and global energy minimization method were verified for 96 and 36 peptides studied by NMR spectroscopy an aqueous solution and in the presence of micelles, respectively, and for 30 mostly a -helical proteins.  Currently, we are working to develop and verify a similar set of b-sheet potentials, and to design a general optimization strategy that reproduces growth and assembly of secondary and supersecondary structures during protein folding.