Empirical Scale of Side-Chain Conformational Entropy in Protein Folding

• Published in: Journal of molecular biology Vol. 231; no. 3; pp. 825 - 839
• Main Authors: Pickett, Stephen D., Sternberg, Michael J.E.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 05.06.1993; Elsevier
• Subjects: Biological and medical sciences; chi angles; Conformational dynamics in molecular biology; free energy; Fundamental and applied biological sciences. Psychology; hydrophobicity; Models, Chemical; Molecular biophysics; mutagenesis; Protein Conformation; Protein Folding; protein mobility; Thermodynamics; Water - chemistry; X-Ray Diffraction; protein mobility; hydrophobicity; free energy; mutagenesis; chi angles; Proteins; Thermodynamics; Side chain; Hydrophobicity; Conformational dynamics
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1006/jmbi.1993.1329

A major effect in the energetics of protein folding is the loss of conformational entropy of the side-chains. The definition of entropy as the Boltzmann sampling over all states ( S = - RΣ p i ln p i) requires evaluation of the probability ( p i) of the system being in rotameric state i. The principle of this paper is to obtain an estimate of p i from the observed distribution of exposed side-chain rotamers in 50 non-homologous protein crystal structures. However because of limited data we show that for all side-chains except Asn, Asp and Glu the side-chain distribution is independent of burial and accordingly all data were pooled in the calculation of p i. For Asn, Asp and Glu side-chains with relative accessibility >60% were used. The scale includes effects due to the symmetry of side-chains such as Phe and the free rotation on side-chain amide, carboxyl and hydroxyl groups. An empirical scale for the loss of side-chain conformational entropy during protein folding is thereby obtained. Values of the change in free energy due to entropy (- TΔ S) on burying a side-chain range from 0 for Ala, Gly and Pro to +2·1 kcal/mol for Gln ( T = 300K). We explore the consistency of a simple model for protein folding that includes side-chain entropy, main-chain entropy, hydrophobicity and hydrogen bonding. The stability of site-directed mutations is discussed in terms of conformational entropy.