Protein-protein interactions create new properties to the interacting components and to the whole system, and it is an important aspect of the biological machinery (1, 2). We present a new method for computer simulations of formation of protein-protein complexes in a cell environment. The method is based on Brownian dynamics, which makes it possible to simulate association reactions of several hundreds of protein pairs in sub-cellular compartments, and to obtain the real-time dynamics of protein-protein interactions. The method allows us to explore the effect of electrostatic forces on the protein-protein complex formation, evaluate the kinetic rate constants, and to unmask the molecular interactions (diffusion, electrostatic interactions) underlying the dynamics of processes in a cell. Biomolecular simulations were used to study the kinetics of protein-protein interactions between the electron transport proteins involved in photosynthesis, plastocyanin–cytochrome f complex, both for wild-type and mutant plastocyanins. The method describes accurately binding interactions for different values of ionic strength in the solution (3) and in the chloroplast thylakoid lumen (4), while taking into account (b) electrostatic interactions between proteins and in the thylakoid membrane (5), (c) kinetic characteristics of ferredoxin and ferredoxin:NADP–reductase complex formation in solution (6), and (d) complex formation of the transmembrane pigment-protein complex Photosystem I and proteins plastocyanin and ferredoxin (7). The developed method can also be used as a predictive tool to resolve the binding sites and to describe complex structures for a range of protein (8). Biomolecular simulation was accelerated on a Graphics Processing Unit (GPU) to describe interactions among a large number of proteins. The 10-100-fold computational acceleration, attained on the GPU device, enabled us calculate the kinetic rates of protein-protein complex formation under the physiologically relevant conditions of sub-cellular environment.

References

1. L. K. Chang , J. H. Zhao, H. L. Liu, J. W. Wu, C. K. Chuang, K. T. Liu, J. T. Chen, W. B. Tsai, Y. Ho, J Biomol Struct Dyn 28, 39-50 (2010).
2. M. J. Aman, H. Karauzum, M. G. Bowden, and T. L. Nguyen. J Biomol Struct Dyn 28, 1-12 (2010).
3. I. B. Kovalenko, A. M. Abaturova, P. A. Gromov, D. M. Ustinin,. E. A. Grachev, G. Y. Riznichenko, A. B. Rubin, Phys. Biol. 3, 121–129 (2006).
4. I. B. Kovalenko, A. M. Abaturova, P. A. Gromov, D. M. Ustinin, G. Y. Riznichenko, E. A. Grachev, A. B. Rubin, Biophysics 53, 140–146 (2008).
5. O. S. Knyazeva, I. B. Kovalenko, A. M. Abaturova, G. Y. Riznichenko, E. A. Grachev, A. B. Rubin, Biophysics 55, 221–227 (2010).
6. I. B. Kovalenko, A. N. Diakonova , A. M. Abaturova, G. Y. Riznichenko, A. B. Rubin, Phys. Biol. 7, 026001 (2010).
7. I. B. Kovalenko, A. M. Abaturova, G. Y. Riznichenko, A. B. Rubin, BioSystems, doi: 10.1016/j.biosystems.2010.09.013 (2010).
8. I. B. Kovalenko, A. B. Abaturova, G. Y. Riznichenko G.Y., Rubin A.B., Dokl. Biochem. Biophys. 427, 215–217 (2009).