Molecular recognition is strongly influenced by the structural flexibility of the binding partners. However, the mobility of a protein binding site is rarely considered in depth in the design of new inhibitors since the information on structural variations is usually limited in crystallographically determined structures. We have developed an automated workflow that enables the dynamics of a protein binding site of interest to be explored computationally and helps to reveal binding pockets or sub-pockets that may open transiently due to internal motion of the protein<sup>1</sup>. The workflow includes the analysis the flexibility of the protein, the simulation of pocket dynamics, and the identification and characterization of the shapes and physico-chemical properties of transient pocket regions.  Several methods, with different degrees of accuracy, are implemented for the simulation of protein flexibility to reveal potential structural changes in binding pockets arising from short and long-time scale protein motions. Particularly, the recently developed Langevin Rotamerically Induced Perturbation (L-RIP) approach is employed to explore  protein binding site motions that normally occur on or beyond the microsecond time scale. The workflow is implemented in the TRAPP webserver (TRansient Pocket in Proteins) and is freely available at http://trapp.h-its.org.<br/>

Exploring target flexibility for drug design

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.