Quantum mechanical study of the conformational behavior of proline and 4R-hydroxyproline dipeptide analogues in vacuum and in aqueous solution

The conformational behavior of the title compounds has been investigated by Hartree–Fock, MP2, and DFT computations on the most significant structures related to variations of the backbone dihedral angles, cis/trans isomerism around the peptide bond, and diastereoisomeric puckering of the pyrrolidin...

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Bibliographic Details
Published in:Journal of computational chemistry 2002-02, Vol.23 (3), p.341-350
Main Authors: Benzi, Caterina, Improta, Roberto, Scalmani, Giovanni, Barone, Vincenzo
Format: Article
Language:English
Subjects:
Dipeptides - chemistry
Hydrogen Bonding - drug effects
Hydroxyproline - chemistry
Models, Molecular
Molecular Conformation
Proline - chemistry
Protein Structure, Secondary - drug effects
Quantum Theory
Solvents - pharmacology
Stereoisomerism
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Summary:The conformational behavior of the title compounds has been investigated by Hartree–Fock, MP2, and DFT computations on the most significant structures related to variations of the backbone dihedral angles, cis/trans isomerism around the peptide bond, and diastereoisomeric puckering of the pyrrolidine ring. In vacuum the reversed γ turn (γl), characterized by an intramolecular hydrogen bridge, corresponds to the absolute energy minimum for both puckerings (up and down) of the pyrrolidine ring. An additional energy minimum is found in the helix region, but only for an up puckering of the pyrrolidine ring. When solvent effects are included by means of the polarizable continuum model the conformer observed experimentally in condensed phases becomes the absolute minimum. The down puckering is always favored over its up counterpart, albeit by different amounts (0.4–0.5 kcal/mol for helical structures and about 2 kcal/mol for γl structures). In helical structures cis arrangements of the peptide bond are only slightly less stable than their trans counterparts. This is no longer true for γl structures, because the formation of an intramolecular hydrogen bond is possible only for trans peptide bonds. In most cases, proline and hydroxyproline show the same general trends; however, the electronegative 4(R) substituent of hydroxyproline leads to a strong preference for up puckerings irrespective of the backbone conformation. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 341–350, 2002
ISSN:0192-8651
1096-987X
DOI:10.1002/jcc.10015