Method to assess packing quality of transmembrane alpha-helices in proteins. 1. Parametrization using structural data

J Chem Inf Model. May-Jun 2007;47(3):1150-62. doi: 10.1021/ci600516x. Epub 2007 Mar 20.

Abstract

Integral membrane proteins (MPs) are pharmaceutical targets of exceptional importance. Modern methods of three-dimensional protein structure determination often fail to supply the fast growing field of structure-based drug design with the requested MPs' structures. That is why computational modeling techniques gain a special importance for these objects. Among the principal difficulties limiting application of these methods is the low quality of the MPs' models built in silico. In this series of two papers we present a computational approach to the assessment of the packing "quality" of transmembrane (TM) alpha-helical domains in proteins. The method is based on the concept of protein environment classes, whereby each amino acid residue is described in terms of its environment polarity and accessibility to the membrane. In the first paper we analyze a nonredundant set of 26 TM alpha-helical domains and compute the residues' propensities to five predefined classes of membrane-protein environments. Here we evaluate the proposed approach only by various test sets, cross-validation protocols and ability of the method to delimit the crystal structure of visual rhodopsin, and a number of its erroneous theoretical models. More advanced validation of the method is given in the second article of this series. We assume that the developed "membrane score" method will be helpful in optimizing computer models of TM domains of MPs, especially G-protein coupled receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane / chemistry*
  • Models, Molecular
  • Protein Folding
  • Protein Structure, Secondary*
  • Rhodopsin / chemistry

Substances

  • Rhodopsin