|
|
|
|
|
|
| About Emil Alexov (Clemson University) |
|
Dr. Emil Alexov his MS in Physics in 1984 from Sofia University, Bulgaria. Four years latter, in 1990, Dr. Alexov received a PhD in plasma physics from Sofia University as well. From 1990 he was an assistant professor at the Department of General Physics at Sofia University and then in 1992 he joined the Bulgarian Academy of Sciences as a scientist in the Institute of Organic Chemistry. In the period 1994-1995 Dr. Alexov was a visiting scientist, STA fellow, at The Institute of Physical and Chemical Research (RIKEN), Japan. In 1995 he came to the United States as a research associate at the Department of Physics, City College of New York. Under the supervision of Prof. Marilyn Gunner, he co-developed the Multi Conformation Continuum Electrostatics (MCCE) method. At the present time, MCCE is the most popular method of calculating pKa’s accounting for alternative positions of the side chains, structured waters and ligands. In 2000 Dr. Alexov joined Columbia University, New York as a Howard Hughes bioinformatics specialist. In the laboratory of Prof. Barry Honig, he was involved in further development and testing of Delphi (the popular finite-difference Poisson-Boltzmann solver). At the same time, Dr. Alexov was participating in the ongoing efforts of the lab in structural modeling using homology-based methods. In 2005 he joined the Department of Physics, Clemson University as an associate professor. He is currently working in the area of protein-protein interactions, which includes developing methods for 3D structure predictions of receptor-ligand complexes and modeling the phenomena associated with protein-protein binding. He is also interested in modeling the effects of SNPs on protein-protein association and their correlations with diseases. He is currently developing computational methods for predicting the binding free energy taking into account conformation and ionization changes. Dr. Alexov is an editorial board member of Computational Biology and Chemistry: Advances and Applications and The Open Chemical and Biomedical Methods Journal. He is an author of more than 50 peer reviewed journal papers.
|
|
Modeling Ionization States and Proton Uptake/Release in Receptor-Ligand Association
Emil Alexov, Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA
Ionized groups carry net charge and thus play a major role in the electrostatic interactions between the ligand and receptor. However, their ionization states depend on such factors as the pH of the water phase, the interactions with other charges, water molecules and mobile ions. Therefore the charge states of the titratable groups have to be predicted prior to applying docking protocols. With the progress made in structural modeling, many structures are expected to be models and therefore the method of computing pKa’s should be able to tolerate structural imperfections while retaining high accuracy predictions. In addition, the formation of the receptor-ligand complex could dramatically change the electrostatic environment of the ionizable groups and cause proton uptake/release. Accounting for such phenomena can be critical for obtaining correct docking solutions. Here we report our recent investigation of applying Multi-Conformation Continuum Electrostatics (MCCE) method to calculate pKa’s of ionizable groups of more than 500 3D structural models of nucleoside mono-phosphate kinases. The proton uptake/release is modeled using 2,887 protein-protein complexes extracted at 40% sequence identity from the ProtCom database. It was shown that in the vast majority of the cases, the formation of a complex induces charge transfer from the water to the protein, resulting in pH dependence of the binding energy. Detailed analysis was performed in case of pepstatin binding to three aspartic proteases and it was demonstrated that ionization changes caused by the complexation could be distributed over the entire structures and are not located only within the binding epitope.
|
|
|
|
|
|
|
|
|
