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Computational Mutagenesis of E. coliLac Repressor: Insight into Structure-Function Relationships and Accurate Prediction of Mutant Activity

  • Majid Masso
  • Kahkeshan Hijazi
  • Nida Parvez
  • Iosif I. Vaisman
Part of the Lecture Notes in Computer Science book series (LNCS, volume 4983)

Abstract

A computational mutagenesis methodology that utilizes a four-body, knowledge-based, statistical contact potential is applied toward quantifying relative changes (residual scores) to sequence-structure compatibility in E. coli lac repressor due to single amino acid residue substitutions. We show that these residual scores correlate well with experimentally measured relative changes in protein activity caused by the mutations. The approach also yields a measure of environmental perturbation at every residue position in the protein caused by the mutation (residual profile). Supervised learning with a decision tree algorithm, utilizing the residual profiles of over 4000 experimentally evaluated mutants for training, classifies the mutants based on activity with nearly 79% accuracy while achieving 0.80 area under the receiver operating characteristic curve. A trained decision tree model is subsequently used to infer the levels of activity for all remaining unexplored lac repressor mutants.

Keywords

lac repressor Delaunay tessellation statistical potential computational mutagenesis supervised learning 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Majid Masso
    • 1
  • Kahkeshan Hijazi
    • 1
  • Nida Parvez
    • 1
  • Iosif I. Vaisman
    • 1
  1. 1.Laboratory for Structural BioinformaticsGeorge Mason UniversityManassasUSA

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