Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

17-POS Board 17 Coarse-grained Modelling of Conformational Changes in Focal Adhesion Kinase upon Oligomerization Csaba Daday 1,2 , Frauke Gräter 1,2 . 1 Heidelberg Institute for Theoretical Studies, Heidelberg, Baden-Württemberg, Germany, 2 Heidelberg University, Heidelberg, Baden-Württemberg, Germany. Focal adhesion kinase (FAK) is a membrane-bound protein found in focal adhesion sites, the kinase domain of which is autoinhibited in equilibrium by the so-called FERM domain. It has been observed experimentally that FAK is recruited by PIP2, a highly negative lipid, and this binding is accomplished through a basic patch of the protein (four cationic residues). In previous work, we have shown in conjunction with FRET experiments that small conformational changes of FAK happen upon binding PIP2[1], although significant mechanical force as well as the PIP2 binding is also required to activate the kinase domain[2]. In recent experiments (unpublished data) it has also been shown that FAK can form regular assemblies on PIP2-enriched membranes, with potential effects on its conformation and activity. We perform large-scale coarse-grained (CG) simulations on 25 copies of FAK on a PIP2- enriched membranes to observe and further understand FAK clustering. We find spontaneous FAK oligomerization with implications for FAK's scaffolding function at focal adhesions. Our data also point to a too strong protein-PIP2 interaction in the MARTINI force field, for which we suggest a correction. [1] Zhou J, Bronowska A, Le Coq J, Lietha D, and Gräter F, Biophys J. 108 (2015): 698-705. [2] Zhou J, Aponte-Santamaría C, Sturm S, Bullerjahn JT, Bronowska A, and Gräter F, PLoS Comput Biol 11 (2015): e1004593.

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