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CEITEC Structural Biology Seminar Series

CEITEC Structural Biology Seminar Series

You are cordially invited to the lecture "Modelling structure, afinity and specificity of biomolecular complexes" delivered by Alexandre MJJ Bonvin, Computational Structural Biology Group, Department of Chemistry, Faculty of Science, Utrecht University,The Netherlands.

WHEN: October 16, 2014 from 14:00
WHERE: Seminar room 1.32, pavilion A11, University Campus Bohunice, Brno

Abstract:

Biomolecular interactions underlie most cellular processes, including signal transduction and apoptosis. Understanding how the cell works requires describing these at molecular level, which is bound to have a dramatic impact on current and future structure-based drug design. Computational methods may assist in this task, particularly when some experimental data can be obtained.

I will describe our information-driven docking approach HADDOCK, illustrating it with various examples including results from the CAPRI blind docking experiment. I will then discuss the problem of binding affinity prediction, showing that current scoring functions in macromolecular docking fail at predicting the affinity of protein-protein complexes. For binding affinity calculation, the surface buried upon complexation is not the absolute determinant and inclusion of additional structural parameters, previously neglected is deemed mandatory for near-accurate predictions. Related to affinity, understanding the structural determinant of specificity is another challenging problem which I will illustrate showing how a conserved Asp to Glu mutation can switch the specificity profile of ubiquitination enzymes. In conclusion, current biophysical models are far more adequate in predicting accurate conformations of protein-protein complexes rather than assessing the affinity and specificity of their interactions.

References:

  • E. Karaca & A.M.J.J. Bonvin. Advances in integrated modelling of biomolecular complexes. Methods 59, 372-381 (2013).
  • P.L. Kastritis & A.M.J.J. Bonvin. Molecular origins of binding affinity: Seeking the Archimedean point. Curr. Opin. Struct. Biol. 23, 868-877 (2013).
  • S.J.L. de Vries, A.S.J. Melquiond, S.J. de Vries, H.Th.M Timmers & A.M.J.J. Bonvin. Dynamic control of selectivity in E2-E3 interactions via a salt-bridge network revealed by an ASP to GLU substitution. PLoS Comp. Biol., 8(11), e1002754 (2012).
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