This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lei, H. Articles by Smith, P. E. Search for Related Content PubMed PubMed Citation Articles by Lei, H. Articles by Smith, P. E.

The Role of the Unfolded State in Hairpin Stability

Department of Biochemistry, Kansas State University, Manhattan, Kansas 66506-3702

Correspondence: Address reprint requests to Paul E. Smith, Dept. of Biochemistry, 36 Willard Hall, Kansas State University, Manhattan, KS 66506-3702. Tel.: 785-532-5109; Fax: 785-532-7278; E-mail: pesmith{at}ksu.edu.

The effects of a T3S mutation on the stability of a 3:5 ß-hairpin forming peptide (YITNSNGTWT) are investigated. Molecular dynamics simulations in explicit water indicate that the wild-type peptide forms a stable hairpin whereas the T3S mutant does not, in agreement with the experimental data. Thermodynamic integration calculations for the mutation of Thr to Ser suggest that the free-energy changes in the folded state are small, but the corresponding changes in the unfolded state are large and favorable. One of the main reasons for the difference appears to be the formation of a stable cluster involving the Tyr1 and Ser3 hydroxyl groups and their interaction with the C-terminal carboxylate group, which was observed after unfolding of the T3S mutant. Further analysis of the side-chain preferences of Thr and Ser indicate that the corresponding cluster in the wild-type peptide is unstable due to the high preference of the Thr ¹ dihedral for g⁺ states, which appeared to be incompatible with formation of a stable cluster. The results suggest that one should consider the nature of the unfolded state when attempting to fully explain the effects of mutations on hairpin stability.