Investigating the dynamic aspects of drug-protein recognition through a combination of MD and NMR analyses: implications for the development of protein-protein interaction inhibitors.

Massimiliano Meli,Giorgio Colombo,Laura Ragona,Katiuscia Pagano

doi:10.1371/journal.pone.0097153

Abstract

In this paper, we investigate the dynamic aspects of the molecular recognition between a small molecule ligand and a flat, exposed protein surface, representing a typical target in the development of protein-protein interaction inhibitors. Specifically, we analyze the complex between the protein Fibroblast Growth Factor 2 (FGF2) and a recently discovered small molecule inhibitor, labeled sm27 for which the binding site and the residues mainly involved in small molecule recognition have been previously characterized. We have approached this problem using microsecond MD simulations and NMR-based characterizations of the dynamics of the apo and holo states of the system. Using direct combination and cross-validation of the results of the two techniques, we select the set of conformational states that best recapitulate the principal dynamic and structural properties of the complex. We then use this information to generate a multi-structure representation of the sm27-FGF2 interaction. We propose this kind of representation and approach as a useful tool in particular for the characterization of systems where the mutual dynamic influence between the interacting partners is expected to play an important role. The results presented can also be used to generate new rules for the rational expansion of the chemical diversity space of FGF2 inhibitors.

Highlights

Protein-protein interactions (PPIs) are the key nodes of cellular circuitries underlying the regulation of most biological processes
The small molecule is bound to the target in one preferential conformation, which is optimally represented by one single structure of the complex: possible pockets that can be reached and favorable interactions that can be established with the target are in general evident and are used to guide the addition/modification of functional groups on the starting scaffold in drug design efforts
Combining the information obtained by the two approaches has the potential to provide relevant novel insight into the structural and conformational properties of dynamic complexes, such as those formed by large, flat and flexible protein surfaces and small molecules aimed at breaking protein-protein interactions

Summary

Introduction

Protein-protein interactions (PPIs) are the key nodes of cellular circuitries underlying the regulation of most biological processes. Combining the information obtained by the two approaches has the potential to provide relevant novel insight into the structural and conformational properties of dynamic complexes, such as those formed by large, flat and flexible protein surfaces and small molecules aimed at breaking protein-protein interactions.

Results

Conclusion