Reverse turns in blocked dipeptides are intrinsically unstable in water

doi:10.1016/0022-2836(90)90399-7

Journal of Molecular Biology

Volume 216, Issue 3, 5 December 1990, Pages 783-796

https://doi.org/10.1016/0022-2836(90)90399-7 Get rights and content

Abstract

We have carried out molecular dynamics simulations to study the conformational equilibria of two blocked dipeptides, Ac-Ala-Ala-NHMe and trans-Ac-Pro-Ala-NHMe, in water (Ac, amino-terminal blocking group COCH₃; NHMe, carboxy-terminal blocking group NHCH₃). Using specialized sampling techniques we computed free-energy surfaces as functions of a conformation co-ordinate that corresponds to hydrogen-bonded reverse turns at small values and to extended conformations at large values. The free-energy difference between hydrogen-bonded reverse turn conformations and extended conformations, determined from the equilibrium constants for reverse turn unfolding, is approximately −5 kcal/mole for Ac-Ala-Ala-NHMe, and −10 kcal/mole for Ac-Pro-Ala-NHMe. These results demonstrate that reverse turns in blocked dipeptides are intrinsically unstable in water. That is, in the absence of strongly stabilizing sequence-specific inter-residue interactions involving side-chains and/or charged terminal groups, the extended conformations of small peptides are highly favored in solution. By thermodynamically decomposing the free-energy differences, we found that the peptide-water entropy is the primary reason for the exceptional stability of the extended conformations of both peptides, and that the differences between the two peptides are primarily due to differences in the peptide-water interactions. In addition, we assessed the “proline effect” on the conformational equilibria by comparing the differences in configurational entropies between the reverse turn and extended conformations of the two peptides. As expected, the extended conformation of the Pro-Ala peptide is destabilized by reduced configurational entropy, but the effect is negligible in the blocked dipeptides. Finally, we compared our results with the results of several other experimental studies to identify some of the specific interactions that may be responsible for stabilizing reverse turns in small peptides in solution.

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^☆: This work was partially supported by an NIH grant to C.L.B. (GM37554). D.J.T. was supported by an NIH predoctoral training grant, and S.F.S. by the Office of Naval Research graduate fellowship program. The Pittsburgh Supercomputer Center and Cray Research, Inc. generously provided the computer time.

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Journal of Molecular Biology

ArticleReverse turns in blocked dipeptides are intrinsically unstable in water☆

Abstract

J. Mol. Biol

J. Mol. Biol

Biophys. J

Advan. Protein Chem

J. Comput. Phys

J. Mol. Biol

Microfolding: Conformational Probability Map for the Alanine Dipeptide in Water from Molecular Dynamics Simulations

Proteins

Models of Thioredoxin Hairpin Structures: Conformational Properties of β-turn Containing Sequences

Biopolymers

Configuration Entropy of the Alanine Dipeptide in Vacuum and in Solution: A Molecular Dynamics Study

J. Am. Chem. Soc

CHARMM: A Program for Macromolecular Energy, Minimization and Dynamics Calculations

J. Comput. Chem

Empirical Predictions of Protein Conformation

Annu. Rev. Biochem

J. Mol. Biol

Comparison of Simple Potential Functions for Simulating Liquid Water

J. Chem. Phys

Method of Estimating the Configurational Entropy of Macromolecules

Macromolecules

Folding of Polypeptide Chains in Proteins: A Proposed Mechanism for Folding

Enhanced Protein Thermostability from Site-directed Mutations that Decrease the Entropy of Unfolding

Article
Reverse turns in blocked dipeptides are intrinsically unstable in water☆