Efficient free energy and enhanced sampling calculations of protein-protein interactions
Abstract
Modern molecular life sciences place a large emphasis on the complex interactions between proteins and corresponding networks. In the pharmaceutical sciences, the focus is shifted from small-molecule drugs to so-called ‘biologicals’, which may be complex protein systems. Computational descriptions of such interactions lead to insight at the molecular level and predictions of affinities between proteins open the way to the rational design of novel therapeutics. An accurate description of protein-protein interactions and the relevant free energy differences crucially depend on appropriate sampling of all relevant conformational states, both in the bound as well as in the unbound state of the binding partners. While relatively efficient computational tools have been described for the interactions between proteins and small molecules, the protein-protein interactions pose additional challenges due to the large diversity in amino acid sequences and the intrinsic flexibility of protein structures. Another challenge is posed by proteins of which parts seem to be intrinsically disordered. In the current proposal, an international, interdisciplinary team of researchers suggests to develop efficient free energy methods and enhanced sampling tools to compute the binding free energy for complex protein systems. As a model system, the 14-3-3 family of proteins and their interaction with tyrosine hydroxylase is selected. In the unbound state, the relevant region in tyrosine hydroxylase is intrinsically disordered, and the affinity for many different sequences is to be evaluated. NMR experiments will be supported by Hamiltonian and Temperature Replica Exchange Molecular Dynamics simulations to describe the conformational ensemble of the partner protein, while the third-power fitting / one-step perturbation method will be extended to develop an universal model to compute the free energy differences between amino acids, allowing for an efficient prediction of binding affinities. The binding process itself will be described using Hamiltonian replica exchange calculations, in combination with distance field distance restraints. Overall, the developed methods will be applicable for a wide variety of protein-protein interactions and the enhanced sampling tools will allow for the calculation of complex potential of mean force profiles to describe the interaction between very flexible molecules.
keywords Conformational sampling 14-3-3 proteins Free energy calculations NMR of intrinsically disordered proteins Binding affinity
Publikationen
Project staff
Chris Oostenbrink
Univ.Prof. Dr. Chris Oostenbrink
chris.oostenbrink@boku.ac.at
Tel: +43 1 47654-89401, 89411, 89419
BOKU Project Leader
01.01.2015 - 31.05.2018
BOKU partners
External partners
Masaryk University
Dr. Jozef Hritz
partner