Research interests

My research interests lie in computational modeling of processes in biomolecular systems and in the bio-inorganic interface.

The current and some recent projects I have been working on are as follows:

  • Transient Pockets in Proteins (TRAPP)

    We have developed a perturbation approach to explore long-time scale conformational motions of proteins. This approach is based on the idea that system equilibration can more efficiently explore local energy minima and transition pathways between them when starting from a distribution over perturbed states rather than from the global minimum of the system. The method has been implemented as a part of the workflow for predicting of transient protein binding pockets (http://trapp.h-its.org/)

  • In Silico prediction of relative drug-protein binding kinetics

    We have adapted the Random Accelerated MD (RAMD) method for prediction relative dissociation rate of drug-protein complexes. The method is based on non-equilibrium MD simulations, where an additional small randomly oriented force is applied to speed up ligand dissociation. This technique provides estimation of the relative residence time and gives insight into the nature of the transition barrier, which can be used for rational design of new slowly dissociating inhibitors.

  • Effect of target conformational flexibility on the ligand binding thermodynamics and kinetics

    In collaboration with the experimental Biophysics group of Merck KGaA, Darmstadt, we explored the effect of the protein flexibility on the thermodynamics and kinetics of the of small molecular compounds binding to N-terminal domain of heat shock protein, HSP90. Particularly we computed dependence of the binding entropy on the type of small molecular compound and on the conformation of the protein binding site. This study demonstrated that the binding of slow dissociation and high affinity drug-like molecules is mainly entropically driven by the conformational flexibility of the protein in the ligand-bound state, rather than the commonly considered solvent-mediated entropic contributions or enthalpic factors.

     

  • Protein adsorption on inorganic surfaces

    In the EU-funded PROSURF project we proposed a model of an implicit solvent force field for simulation of protein adsorption on solid surfaces. We have it for the Au(111) surface and implemented  in the BD simulation program SDA (Simulation of Diffusional Association, http://mcm.h-its.org/sda).

  • Multi-scale modeling of adsorption process

    To describe the long time-scale behavior of the adsorption process, which include the protein-solid surface recognition and the following protein structural adaptation on a surface, we employed a combination of the MM BD approach and MD simulations. This approach was applied to study ubiquitin binding to Nanoparticles, Lysozyme adsorption on a silica-like surface, and recognition of the gold surface by BLIP protein with different tripeptide tags.

     

Current Project

IMI JU (Innovativ Medicine Initiative Join Undertaken) K4DD (Kinetics for Drug Discovery)

Developed Methods/Software

  • TRAPP – TRAnsient Pockets in Protein – http://www.mcm.h-its.org/trapp
    • program package for simulation, analysis, and visualization of protein cavity dynamics and for detection of transient sub-pockets using protein motion trajectories or ensembles of protein structures.
  • L-RIP & RIPlig  – http://mcm.h-its.org/lrip-riplig
    •  two non-equilibrium MD approaches aimed at identification of slow conformational changes of a protein binding site
  • ProMetCS – protein-metal continuum solvent force field; implemented in SDA – Simulation of Diffusional Association packet – http://mcm.h-its.org/sda7

Education

 Ph.D. in Physics and Mathematics, St. Petersburg State University, Russia

Professional experience

2009-present  Molecular and Cellular Modeling Group of Prof. R.C. Wade, HITS, Heidelberg, Germany
2002-2009  Theoretical Chemistry group of Prof. R. J. Buenker; Wuppertal University, Germany
2000-2002  Fellow of the Alexander von Humboldt Foundation. Theoretical Chemistry group of Prof. R. J. Buenker, Wuppertal University, Germany

1995-2000  Molecular Photonics Group of Prof. I. P. Vinogradov; Department of Physics, St. Petersburg State University, Russia

Publications

see Google Scholar