PubMed · 9868366
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R J Ellis, C Dobson, U Hartl. 1998. Sequence does specify protein conformation.. https://doi.org/10.1016/s0968-0004(98)01324-3
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The packing of alpha-helices in proteins is restricted by both the principle of close packing and the chemical nature of side chains. As a result, (1) alpha-helical surfaces forming the interface should be complementary to each other, (2) hydrophobic stripes of the alpha-helices should fit together like pieces of a jigsaw puzzle, and (3) buried polar side chains (if there are any) should be arranged in a complementary fashion.
A coarse-grained dynamic Monte Carlo (MC) simulation method is used to investigate the conformational dynamics of chymotrypsin inhibitor 2 (CI2). Each residue is represented therein by two interaction sites, one at the alpha-carbon and the other on the amino acid side-chain. The energy and geometry parameters extracted from databank structures are used. The calculated rms fluctuations of alpha-carbon atoms are in good agreement with crystallographic temperature factors. The two regions of the protein that pack against each other to form the main hydrophobic core exhibit negatively correlated fluctuations. The conformational dynamics could efficiently be probed by the time-delayed orientational and conformational correlation functions of the virtual bonds: the active site loop, excluding the active site bond, the turn region, and the N-terminal of the alpha-helix are relatively more mobile regions of the structure. A correlation is observed between the hydrogen/deuterium (H/D) exchange behavior and the long-time orientational and conformational autocorrelation function values for CI2. A cooperativity in the rotations of the bonds near in sequence is observed at all time windows, whereas the cooperative rotations of the bonds far along the sequence appear at long time windows; these correlations contribute to the stability of the secondary structures and the tertiary structure, respectively.
This article is a personal perspective on the developments in the field of protein folding over approximately the last 40 years. In addition to its historical aspects, the article presents a view of the principles of protein folding with particular emphasis on the relationship of these principles to the problem of protein structure prediction. It is argued that despite much that is new, the essential elements of our current understanding of protein folding were anticipated by researchers many years ago. These elements include the recognition of the central importance of the polypeptide backbone as a determinant of protein conformation, hierarchical protein folding, and multiple folding pathways. Important areas of progress include a detailed characterization of the folding pathways of a number of proteins and a fundamental understanding of the physical chemical forces that determine protein stability. Despite these developments, fold prediction algorithms still encounter difficulties in identifying the correct fold for a given sequence. This may be due to the possibility that the free energy differences between at least a few alternate conformations of many proteins are not large. Significant progress in protein structure prediction has been due primarily to the explosive growth of sequence and structural databases. However, further progress is likely to depend in part on the ability to combine information available from databases with principles and algorithms derived from physical chemical studies of protein folding. An approach to the integration of the two areas is outlined with specific reference to the PrISM program that is a fully integrated sequence/structural-analysis/fold-recognition/homology model building software system.