Proteus and the Design of Ligand Binding Sites.
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 pK α 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, pK α 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.
Theoretical and Computational Biophysics Group, Department of Physics, University of Cyprus, 1678, Nicosia, Cyprus.
Savvas
S
Polydorides
Theoretical and Computational Biophysics Group, Department of Physics, University of Cyprus, 1678, Nicosia, Cyprus.
Eleni
E
Michael
Department of Biology, Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique, 91128, Palaiseau, France.
David
D
Mignon
Department of Biology, Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique, 91128, Palaiseau, France.
Karen
K
Druart
Theoretical and Computational Biophysics Group, Department of Physics, University of Cyprus, 1678, Nicosia, Cyprus. archonti@ucy.ac.cy.
Georgios
G
Archontis
Department of Biology, Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique, 91128, Palaiseau, France. thomas.simonson@polytechnique.fr.
Thomas
T
Simonson
D001665:Binding Sites; D008024:Ligands; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
D008024:Ligands; D011506:Proteins
Generalized Born model; Implicit solvent; Ligand design; Monte Carlo; Protein design