Side-chain entropy opposes α-helix formation but rationalizes experimentally determined helix-forming propensities

Trevor P. Creamer, George D. Rose

Research output: Contribution to journalArticlepeer-review

Abstract

In recent host-guest studies, the helix-forming tendencies of amino acid residues have been quantified by three groups, each obtaining similar results [Padmanabhan, S., Marqusee, S., Ridgeway, T., Laue, T. M. & Baldwin, R. L. (1990) Nature (London) 344, 268-270; O'Neil, K. T. & DeGrado, W. F. (1990) Science 250, 646-651; Lyu, P. C., Liff, M. I., Marky, L. A. & Kallenbach, N. R. (1990) Science 250, 669-673], Here, we explore the hypothesis that these measured helix-forming propensities are due primarily to conformational restrictions imposed upon residue side chains by the helix itself. This proposition is tested by calculating the extent to which the bulky helix backbone "freezes out" available degrees of freedom in helix side chains. Specifically, for a series of apolar residues, the difference in configurational entropy, Δ5, between each side chain in the unfolded state and in the α-helical state is obtained from a simple Monte Carlo calculation. These computed entropy differences are then compared with the experimentally determined values. Measured and calculated values are found to be in close agreement for naturally occurring amino acids and in total disagreement for non-natural amino acids. In the calculation, ΔSAla = 0. The rank order of entropy loss for the series of natural apolar side chains under consideration is Ala < Leu < Trp < Met < Phe < Ile < Tyr < Val. Among these, none favor helix formation; Ala is neutral, and all remaining residues are unfavorable to varying degrees. Thus, applied to side chains, the term "helix preference" is a misnomer. While side chain-side chain interactions may modulate stability in some instances, our results indicate that the drive to form helices must originate in the backbone, consistent with Pauling's view of four decades ago [Pauling, L., Corey, R. B. & Branson, H. R. (1951) Proc. Natl. Acad. Sci. USA 37, 205-210].

Original languageEnglish (US)
Pages (from-to)5937-5941
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number13
DOIs
StatePublished - Jul 1 1992
Externally publishedYes

Keywords

  • Protein engineering
  • Protein folding
  • α-helix

ASJC Scopus subject areas

  • General

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