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J1-8145 Dynamic aspect of ligand-protein binding


prof. dr. Simona Golič Grdadolnik (KI)



dr. Franc Avbelj (KI)

prof. dr. Jože Grdadolnik (KI)

prof. dr. Franci Merzel (KI)

dr. Francesca Paoletti (KI)

Iza Ogris (KI)

Marko Sever (KI)

prof. dr. Stanko Gobec (FFA)

dr. Martina Hrast (FFA)

dr. Damijan Knez (FFA)


Period: 05.2017-04.2020



A variety of processes essential to living organisms involve ligand-protein binding, where the ligands are switching proteins between different functional states. The atomic resolution structures of ligand-protein complexes provide the basis for the understanding of ligand-protein interactions. However, it is becoming obvious that dynamic processes are playing an important role in the mechanism of ligand-protein binding. Therefore the combined structural and dynamic characterization of ligand-protein binding is required for the thorough understanding of its mechanism and its functional role in a particular life process. Despite the recent advances in biophysical techniques and computational approaches for the investigation of biomolecular systems, the characterization of dynamic processes remains a demanding challenge due to their elusive nature.

The aim of this project is a site specific characterization of dynamic processes in ligand-protein complexes on a wide time scale at atomic level using a combined approach of nuclear magnetic resonance spectroscopy (NMR), vibrational spectroscopy and molecular dynamics (MD) simulations. The research will consist of a detailed characterization of protein dynamics in ligand-protein complexes, including the involvement of low-populated protein high energy states. Special attention will be paid on the characterization of coupled ligand-protein motions and on a yet very poorly understood relationship between ligand intrinsic flexibility and its biological potency. Our resent results have indicated that beside intrinsic protein motions, these dynamic processes can also severely effect ligand-protein interactions and can be related to ligand functional activities. The capabilities of NMR spectroscopy, to identify and investigate protein motions on a picosecond to millisecond time scale, are well-known. Based on our characterization of highly intrinsically flexible dipeptides in aqueous environments, we believe that vibrational spectroscopy will significantly contribute to the NMR studies through its ability to directly detect short-lived states, especially to the characterization of ligand intrinsic flexibilities. In order to provide a model based understanding of the correlation between individual types of motion and their effect on ligand-protein binding, we will use MD simulations and develop computational tools that will allow the comparison of computational results with the experimental data.

We will investigate ligand binding to Mur ligase D, a multi-domain enzyme protein, which reflects conformational dynamics on a wide range of scales in time and space. The results of these studies will be implemented in the design and development of more potent Mur ligase D inhibitors, which will be synthesized and biologically evaluated. Thus, the potential of our findings for target-based design and discovery of small-molecule drugs will be considered. The general applicability of this new knowledge will be inspected through its application in the investigation of ligand binding to other proteins, sterol 14α-demethylase and nerve growth factor, with up to now not yet fully understood ligand-driven activation mechanisms.

The results of the proposed studies may significantly contribute to the advance of molecular medicine and will be of high interest to many specific research fields, such as molecular recognition, molecular signalling, enzyme catalysis, protein folding, target-based design and discovery of drugs.

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