Knowledge-based potential for positioning membrane-associated structures and assessing residue-specific energetic contributions

Chaim A. Schramm, Brett T. Hannigan, Jason E. Donald, Chen Keasar, Jeffrey G. Saven, William F. Degrado, Ilan Samish

Research output: Contribution to journalArticlepeer-review

Abstract

The complex hydrophobic and hydrophilic milieus of membrane-associated proteins pose experimental and theoretical challenges to their understanding. Here, we produce a nonredundant database to compute knowledge-based asymmetric cross-membrane potentials from the per-residue distributions of C β, Cγ and functional group atoms. We predict transmembrane and peripherally associated regions from genomic sequence and position peptides and protein structures relative to the bilayer (available at http://www.degradolab.org/ez). The pseudo-energy topological landscapes underscore positional stability and functional mechanisms demonstrated here for antimicrobial peptides, transmembrane proteins, and viral fusion proteins. Moreover, experimental effects of point mutations on the relative ratio changes of dual-topology proteins are quantitatively reproduced. The functional group potential and the membrane-exposed residues display the largest energetic changes enabling to detect native-like structures from decoys. Hence, focusing on the uniqueness of membrane-associated proteins and peptides, we quantitatively parameterize their cross-membrane propensity, thus facilitating structural refinement, characterization, prediction, and design.

Original languageAmerican English
Pages (from-to)924-935
Number of pages12
JournalStructure
Volume20
Issue number5
DOIs
StatePublished - 9 May 2012

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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