Method development

Free binding of inhibitor benzamidine to enzyme trypsin

WU tags: TRYP, PYRT

Description

Identification of inhibitor molecules (drugs) that bind to enzymes or other proteins (targets) has been, and will be, the principal goal in drug discovery processes. Computational biologists/biochemists develop computational methods that span from ligand binding pose prediction to ligand binding affinity calculations, to aid in the quest for finding new, better and safer drugs. With our experiments, we show for the first time, a complete process of binding of a drug-like molecule to its target protein. Our molecules are used as a toy model in a proof-of-concept study for future and more relevant cases. In addition to reproduction of crystallographic ligand binding pose (also tackled by much cheaper but more coarse-grained techniques named 'computational docking'), we show the complete pathway of binding that the inhibitor follows from the solvent to the pocket where it binds. We detect several amino-acids in trypsin that consistently interact with benzamidine as it binds, which indicates that there is a prefered pathway for benzamidine to bind and therefore inhibit the function of trypsin. The principal outcome of this work is that with Molecular Dynamics simulations, it is now possible to study full binding events, being able to visualize and quantify the whole process of binding with a single computational experiment. We are confident that this achievement will allow a much deeper understanding of the processes of binding for small drug-like molecules which may then lead to the design of new, better and safer drugs.

Publications

  • I. Buch, T. Giorgino and G. De Fabritiis, Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations, Proc. Natl. Acad. Sci. USA 108(25), 10184-10189 (2011)

Molecular simulations of the SH2 and ligand peptide binding affinity

WU tags: pYEEI, SH2

Description

The SH2 is a protein domain involved in protein-protein interactions. This particular domain plays a major role in cell communication on the sigalling processes for cell growth and development. However, the end goal for running such simulations is not to expand the knowldege on this particular system, but to use it as a model for developing methods to calculate protein-protein binding affinities.
Such methods will be very useful, for example, in the study of why certain wrong forms of proteins stop interacting with other partner proteins, as a way to give explanation to diseases in which these sort of mechanisms occur.

Publications

  • I. Buch, S. K. Sadiq and G. De Fabritiis, Optimized potential of mean force calculations of standard binding free energy, J. Chem. Theory Comput., 7, 1765–1772 (2011)
  • I. Buch, M. J. Harvey, T. Giorgino, D. P. Anderson and G. De Fabritiis, High-throughput all-atom molecular dynamics simulations using distributed computing, J. Chem. Inf. and Mod. 50, 397 (2010)

Forward-Reverse Steered Molecular Dynamics

WU tags: GA

Description

Potassium ion permeation in Gramicidin A. We are giving workunits comprising full-atom simulations of gramidicin A for ion transport, a total of 30,000 atoms. Each workunit lasts less than one day and you have to complete it before 4 days.

Publications

  • T. Giorgino and G. De Fabritiis, A high-throughput steered molecular dynamics study on the free energy profile of ion permeation through gramicidin A, J. Chem. Theory Comput.,7 , 1943–1950 (2011)