Computational Redesign of a Protein-Protein Interface for High Affinity and Binding Specificity Using Modular Architecture and Naturally Occurring Template Fragments

V. Potapov, D. Reichmann, R. Abramovich, D. Filchtinski, N. Zohar, D. Ben Halevy, M. Edelman*, V. Sobolev, G. Schreiber

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

A new method is presented for the redesign of protein-protein interfaces, resulting in specificity of the designed pair while maintaining high affinity. The design is based on modular interface architecture and was carried out on the interaction between TEM1 β-lactamase and its inhibitor protein, β-lactamase inhibitor protein. The interface between these two proteins is composed of several mostly independent modules. We previously showed that it is possible to delete a complete module without affecting the overall structure of the interface. Here, we replace a complete module with structure fragments taken from nonrelated proteins. Nature-optimized fragments were chosen from 107 starting templates found in the Protein Data Bank. A procedure was then developed to identify sets of interacting template residues with a backbone arrangement mimicking the original module. This generated a final list of 361 putative replacement modules that were ranked using a novel scoring function based on grouped atom-atom contact surface areas. The top-ranked designed complex exhibited an affinity of at least the wild-type level and a mode of binding that was remarkably specific despite the absence of negative design in the procedure. In retrospect, the combined application of three factors led to the success of the design approach: utilizing the modular construction of the interface, capitalizing on native rather than artificial templates, and ranking with an accurate atom-atom contact surface scoring function.

Original languageAmerican English
Pages (from-to)109-119
Number of pages11
JournalJournal of Molecular Biology
Volume384
Issue number1
DOIs
StatePublished - 5 Dec 2008
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by Israel Ministry of Science and Technology grant 263 to G.S., M.E., and V.S., and by MINERVA grant 8525 to G.S.

Keywords

  • computational protein design
  • molecular recognition
  • protein-protein interaction
  • structure-based reengineering

Fingerprint

Dive into the research topics of 'Computational Redesign of a Protein-Protein Interface for High Affinity and Binding Specificity Using Modular Architecture and Naturally Occurring Template Fragments'. Together they form a unique fingerprint.

Cite this