Modeling mutations in protein structures

Eric Feyfant, Andrej Sali, Andras Fiser

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

We describe an automated method for the modeling of point mutations in protein structures. The protein is represented by all non-hydrogen atoms. The scoring function consists of several types of physical potential energy terms and homology-derived restraints. The optimization method implements a combination of conjugate gradient minimization and molecular dynamics with simulated annealing. The testing set consists of 717 pairs of known protein structures differing by a single mutation. Twelve variations of the scoring function were tested in three different environments of the mutated residue. The best-performing protocol optimizes all the atoms of the mutated residue, with respect to a scoring function that includes molecular mechanics energy terms for bond distances, angles, dihedral angles, peptide bond planarity, and non-bonded atomic contacts represented by Lennard-Jones potential, dihedral angle restraints derived from the aligned homologous structure, and a statistical potential for non-bonded atomic interactions extracted from a large set of known protein structures. The current method compares favorably with other tested approaches, especially when predicting long and flexible side-chains. In addition to the thoroughness of the conformational search, sampled degrees of freedom, and the scoring function type, the accuracy of the method was also evaluated as a function of the flexibility of the mutated side-chain, the relative volume change of the mutated residue, and its residue type. The results suggest that further improvement is likely to be achieved by concentrating on the improvement of the scoring function, in addition to or instead of increasing the variety of sampled conformations.

Original languageEnglish (US)
Pages (from-to)2030-2041
Number of pages12
JournalProtein Science
Volume16
Issue number9
DOIs
StatePublished - Sep 2007

Fingerprint

Mutation
Dihedral angle
Proteins
Lennard-Jones potential
Molecular Dynamics Simulation
Mechanics
Atoms
Point Mutation
Molecular mechanics
Potential energy
Simulated annealing
Conformations
Molecular dynamics
Peptides
Testing

Keywords

  • Comparative modeling
  • Point mutation
  • Protein structure

ASJC Scopus subject areas

  • Biochemistry

Cite this

Modeling mutations in protein structures. / Feyfant, Eric; Sali, Andrej; Fiser, Andras.

In: Protein Science, Vol. 16, No. 9, 09.2007, p. 2030-2041.

Research output: Contribution to journalArticle

Feyfant, Eric ; Sali, Andrej ; Fiser, Andras. / Modeling mutations in protein structures. In: Protein Science. 2007 ; Vol. 16, No. 9. pp. 2030-2041.
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