Investigation of ligand passage in proteins
Lada Biedermannová1, Zbyněk
Prokop2, Radka Chaloupková2, Pavel Dvořák2,
Jiří Damborský2 and Rebecca Wade1
1. Molecular and Cellular Modeling Group,
HITS gGmbH, Heidelberg, Germany
2. Loschmidt Laboratories, Department of
Experimental Biology and Research Centre for Toxic Compounds in the
Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.
The function of many globular proteins
depends on their interaction with small organic molecules - substrates,
products, cofactors, or inhibitors - as well as the solvent. The interaction
sites, however, are often not located on the surface of the protein, but rather
deeply buried in the structure. In order to understand the function of such
proteins, we need to understand the process in which ligands pass through the
tunnels leading from the bulk solvent to the binding site. Here, we investigate
ligand passage in haloalkane dehalogenase enzyme LinB [1], and the effect of
mutation on it. The Random Acceleration Molecular Dynamics (RAMD) method [2],
developed in our lab, is employed to find the pathways available for the
products of the LinB catalyzed reaction. The free energy profiles of the
product unbinding process are investigated using the Adaptive Biasing Force
(ABF) method [3]. In order to understand the molecular details of the process,
we focus on analyzing the dynamics of solvent molecules during the ligand
passage. The hydration patterns turn out to play an important role in
facilitating the passage of ions.
This project is supported by a
postdoctoral fellowship from DAAD to LB, and grants from the Ministry of
Education of the Czech Republic to ZP (CZ.1.05/2.1.00/01.0001), RCH (LC06010)
and JD (IAA40163090).
1. Chaloupková
R, Sýkorová J, Prokop Z, Jesenská A, Monincová M, Pavlová M, Tsuda M, Nagata Y,
Damborský J.
J Biol. Chem. 278 (2003), 52622-8.
2. Lüdemann
SK, Lounnas V, Wade RC. J Mol Biol. 303 (2000), 797-811.
3. Hénin J, Fiorin G,
Chipot C, Klein ML, J. Chem. Theor. Comp.
6 (2010), 35-47.