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.