Polypeptide chain folding through a highly helical intermediate as a general principle of globular protein structure formation

Abstract

General features of the three-dimensional structures of globular proteins can be explained if it is assumed that at early stages of protein folding the major part of the polypeptide chain is in the a-helical conformation [l]. Analysis of the energy, kinetics and diffusion factors as well as of the general features of the primary structure of globular proteins also suggests the formation of highly helical intermediate globule as a general principle of protein folding. In the present paper the results of such an analysis are briefly summarized. It is deduced that: (i) Short cr-helices bearing hydrophobic clusters on their surfaces must be formed first. (ii) These must then be united into a highly helical intermediate globule. (iii) A native structure must be formed by the subsequent transition of cu-helices of the highly helical intermediate globule into different types of secondary structure (this transition is not .accompanied by any considerable shifts of the material of cu-helices relative to each other). The stereochemical simulation of the formation of a highly helical intermediate and its subsequent transition into another conformation permits one to predict, in good agreement with experiment, threedimensional structures of globular proteins with different ratios of cu-helices and P-sheets [2-61 . The suggested principle of protein folding is a development of Pauling and Corey’s ideas [7] that in the absence of long-range interactions the a-helix is the most preferable conformation for a polypeptide chain. 2. Structural prerequisites