A simplified representation of protein conformations for rapid simulation of protein folding.

This report is one of a series of papers that introduce and use a new and highly simplified treatment of protein conformations. The first paper (Levitt & Warshel, 1975) outlined fhe approach and showed how it could be used to simulate the “renaturation” of a small protein. The present paper describes fhe representation in some detail and tests the methods extensively under a variety of different conditions. The third paper (Warshel & Levitt, 1976) is devoted to a study of the folding pathway and stability of a mainly a-helical protein. In this work, I show how the concept of time-averaged forces, introduced previously (Levitt & Warshel, 1975), can be used to simplify conformafional energy calculations on globular proteins. A detailed description is given of the simplified molecular geometry, the parameterization of suitable force fields, the best energy minimization procedure, and fhe techniques for escaping from local minima. Extensive tests of the method on the native conformation of pancreatic trypsin inhibitor show that the simplifications work well in representing the stable native conformation of this globular protein. Further tests show that simulated folding of pancreatic trypsin inhibitor from open chain conformations gives compact calculated conformations thaf have many features in common with the actual native conformafion. Folding simulafions are done under a variety of conditions, and fhe relevance of such calculations fo the actual in vitro folding process is discussed at some length. These same techniques have many potential applications including enzyme-substrate binding, changes in protein tertiary and quaternary structure, and protein-protein inferactiona.