Detection and characterization of nonspecific, sparsely-populated binding modes for conformational selection in the early stages of complexation

Published: March 18, 2015


Antonio Cardone, Aaron Bornstein, Harish C. Pant, Mary C. Brady, Ram D. Sriram, Sergio Hassan


A method is proposed to study protein-ligand binding in a system governed by specific and non-specific interactions. Strong associations lead to narrow conformational distributions in the proteins configuration space; weak and ultra-weak associations lead instead to broader distributions, a manifestation of non-specific, sparsely-populated binding modes with multiple interfaces. The distributions are used to generate biasing functions for simulations of concentrated multispecies, multiprotein systems from which thermodynamic quantities can be calculated. The method is based on the notion that a discrete set of preferential first-encounter modes are metastable states from which stable (pre-relaxation) complexes at equilibrium evolve. The method can be used to explore alternative pathways of complexation with statistical significance, which has implications for its integration into a general algorithm to study protein interactions networks. The method is applied to a peptide-protein complex. The peptide adopts several low-population conformers in solution and binds in a variety of modes with a broad range of affinities. The system is thus well suited for a discussion of general features of binding, including nonspecific interactions, multiplicity of binding modes, and conformational selection, and to illustrate how the method can be applied to study these problems systematically.
Citation: Journal of Computational Chemistry
Pub Type: Journals


protein-protein association, protein aggregation, complex formation, configurational bias Monte Carlo, nonspecific interactions, solvent effects, implicit solvent model
Created March 18, 2015, Updated November 10, 2018