Modeling of α-MSH conformations with implicit solvent

N. V. Prabhu, J. S. Perkyns, B. Montgomery Pettitt

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

A conformational search for the most probable structures of the hormone α-MSH in aqueous solution was performed in order to help determine the structural features necessary for biological activity. The free-energy surface was modeled using methods from integral equation theory, and high- temperature molecular dynamics was used to enhance conformational sampling. Families of low free-energy structures have been found. The minimum energy structure shows a stable β-turn conformation in the putative message region that is stabilized by a salt bridge between Glu5 and Lys11. The orientation of the side chains reflects the amphophilic nature of the peptide, and a close interaction between the side chains of the His6, Phe7 and Trp9 was observed. Several structural features observed in the minimum energy structure agree well with experimental results. The conformational features led to a hypothesis of a receptor-hormone interaction model in which the hydrophobic side chains of Phe7 and Trp9 interact with the transmembrane portion of the human melanocortin (MC1) receptor. Also, the positively charged side chain of Arg8 and the imidazole side chain of His6 may interact with the negatively charged portions of the receptor which may even be on the receptor's extracellular loops.

Original languageEnglish (US)
Pages (from-to)394-407
Number of pages14
JournalJournal of Peptide Research
Volume54
Issue number5
DOIs
StatePublished - Nov 4 1999

Keywords

  • Integral equations
  • Peptides
  • Potentials of mean force

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

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