|Email: m.ahmad(remove this and add @)bioinformatik.uni-saarland.de
Telephone: ++49 +681 302 70713
Fax: ++49 +681 302 70702
Postal address: Center for Bioinformatics
Gebaeude E2 1, R. 302
P.O. Box 15 11 50
Mechanism of protein-protein interaction
are studying the mechanisms and the driving forces for the formation of protein-protein complexes. the aim of these studies is
understanding the mechanisms of association on the atomistic scale by using extensive molecular dynamics with explicit representation of the water. Our studies showed two main different mechanisms for the association based on the nature of the binding interfaces:
1. the hydrophobic association.
2. the hydrophilic association.
The association of the hydrophilic interfaces:The hydrophilic effect.
Using extensive molecular dynamics (MD) simulations with explicit water representation, we aim to find the basis of atomistic mechanisms during association of hydrophilic interfaces. Our simulations for the binding process of Barnase–Barstar reproducibly recover the native bound state of the complex and thus provide atomistic insight into the mechanism of binding. The water in the interfacial gap forms an adhesive hydrogen-bond network between the hydrophilic protein interfaces. . The dielectric constant in the gap between the proteins is strongly reduced up to distances of a few nanometres. Interestingly, the dielectric properties of the water in the interfacial gap are strongly anisotropic with a preferred directionality for the electrostatic interactions along the direction perpendicular to the interfaces. Therefore, the water solvent between the two proteins makes an important contribution to the electrostatic funnelling of the binding free energy surface for the binding process.
Movie for the association process Barnase-Barstar: Computer simulation of the association process between the two proteins Barnase and Barstar.The movie shows simulation snapshots from a molecular dynamics trajectory covering 430 ns of simulation time.
The hydrophobic dewetting: the case of protein recognition mediated by Proline recognition domains.
We used MD simulation to understand the mechanism of protein recognition mediated by Proline recognition domains especially SH3 and GYF domains. In this project we studied the association of a proline rich peptide to a SH3 domain from diffusion to the final complex through transient encounters. The results reveal a bimodal binding mechanism, where the electrostatic interactions and hydrophobic dewetting work in perfect synergy as driving forces for protein-protein association.
PublicationsAhmad, M., Gu, W., and Helms, V. (2008), Angewandte Chemie, Vol. 120, p. 7738-7742. Mechanismus der schnellen Peptiderkennung durch SH3-Domänen (DE). Angewandte Chemie International Edition, Vol. 47, p. 7626-7630. Mechanism of Fast Peptide Recognition by SH3 Domains (EN).
Ahmad, M., Gu, W., Geyer, T., and Helms, V. (2011) Nature Communications, Vol. 2, Article no. 261. Adhesive water networks facilitate binding of protein interfaces.
News about this work:
"Wasser hilft Proteinen bei der Partnersuche" in scinexx.
Erdmann, F., Schäuble, N., Lang, S., Jung, M., Honigmann, A., Ahmad, M., Dudek, J., Benedix, J., Harsmann, A., Kopp, A., Helms, V., Cavalié, A., Wagner, R., and Zimmermann, R. (2011) EMBO Journal, Vol. 30, p. 17-31. Interaction of calmodulin with Sec61 limits Ca2+ leakage from the endoplasmic reticulum.
Zimmermann, R., Eyrisch, S., Ahmad, M., and Helms, V. (2011) BBA - Biomembranes, Vol. 1808, p. 912-924. Protein translocation across the ER membrane.
Invited and contributed talks
Mechanism of ultra-fast peptide binding to SH3 domains at computer simulation and theory of macromolecules, Hünfeld, Germany (2008).
How do proteins associate? A lesson from SH3 domain at the 4th German Conference on Chemoinformatics, Goslar, Germany (2008). The abstract is published in the Chemistry Central Journal.
Multiple mechanisms of protein- protein interaction at the 24th Molecular Modelling Workshop, Erlangen, Germany (2010).
Adhesive water networks facilitate binding of protein interfaces at the computer simulation and theory of macromolecules, Hünfeld, Germany (2010).
Poster awards at the 24th Molecular Modelling Workshop, Erlangen, Germany (2010).
Cover Story in Angewandte Chemie