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Proteus and the Design of Ligand Binding Sites

  • Savvas Polydorides
  • Eleni Michael
  • David Mignon
  • Karen Druart
  • Georgios ArchontisEmail author
  • Thomas SimonsonEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1414)

Abstract

This chapter describes the organization and use of Proteus, a multitool computational suite for the optimization of protein and ligand conformations and sequences, and the calculation of pKα shifts and relative binding affinities. The software offers the use of several molecular mechanics force fields and solvent models, including two generalized Born variants, and a large range of scoring functions, which can combine protein stability, ligand affinity, and ligand specificity terms, for positive and negative design. We present in detail the steps for structure preparation, system setup, construction of the interaction energy matrix, protein sequence and structure optimizations, pKα calculations, and ligand titration calculations. We discuss illustrative examples, including the chemical/structural optimization of a complex between the MHC class II protein HLA-DQ8 and the vinculin epitope, and the chemical optimization of the compstatin analog Ac-Val4Trp/His9Ala, which regulates the function of protein C3 of the complement system.

Key words

Protein design Ligand design Monte Carlo Implicit solvent Generalized Born model 

Notes

Acknowledgements

GA, SP, and EM acknowledge financial support through a grant offered by the University of Cyprus.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Savvas Polydorides
    • 1
  • Eleni Michael
    • 1
  • David Mignon
    • 2
  • Karen Druart
    • 2
  • Georgios Archontis
    • 1
    Email author
  • Thomas Simonson
    • 2
    Email author
  1. 1.Theoretical and Computational Biophysics Group, Department of PhysicsUniversity of CyprusNicosiaCyprus
  2. 2.Department of BiologyLaboratoire de Biochimie (CNRS UMR7654), Ecole PolytechniquePalaiseauFrance

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