Role of noncovalent interactions in protein peripheral membrane binding. Computational perspectives
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Noncovalent forces are important driving forces in nature particularly in biology, and they dictate many biological processes including the binding of peripheral protein to the cell membrane. The widely acknowledged models describe this process as electrostatics driven membrane adsorption followed by short-range protein-lipid interactions i.e. hydrogen bonds, hydrophobic interactions. Some of the key elements in such models are: clusters of basic residues are essential for electrostatic adsorption, and basic residues contribute equally to the membrane binding. Nevertheless, none of these models account for the role of cation-π interactions in membrane binding. With selected protein candidates, we further explore these models and work towards a generalized description of protein peripheral binding to membranes in terms of noncovalent forces. Our investigation highlights the limitations of these existing descriptions. We demonstrate that the requirement of having a cluster of basic residues is not essential. Further, we show that the contributions of basic residues are distance dependent. In other words, their localization in the membrane-water interface determines their strength and hence is not equal. We also establish the role of tyrosine-choline cation- π interactions in membrane binding of peripheral proteins. We explore in detail the nature of tyrosine-choline mediated cation-π interactions using high-level quantum mechanical calculations. Later, this information is used to improve the description of cation-π interactions in molecular simulation models. These improvements of force field parameters are further tested using molecular dynamics simulations. Finally, we used this information to build an interaction diagram that can be used to better describe the binding of peripheral proteins to the cell membrane. Future testing and the generalization of this diagram will further establish this as a common model.
Består avPaper 1: A.-S. Schillinger, C. Grauffel, H.M. Khan, Ø. Halskau, N. Reuter, "Two homologous neutrophil serine proteases bind to POPC vesicles with different affinities: When aromatic amino acids matter", Biochimica et Biophysica Acta (BBA) – Biomembranes, vol. 1838, pp. 3191-3202, 2014. The article is available at: http://hdl.handle.net/1956/9516
Paper 2: B. Yang, M. Pu, H.M. Khan, L. Friedman, N. Reuter, M.F. Roberts, A. Gershenson, "Quantifying Transient Interactions between Bacillus Phosphatidylinositol-Specific Phospholipase-C and Phosphatidylcholine-Rich Vesicles", Journal of the American Chemical Society, vol. 137, pp. 14-17, 2015. The article is not available in BORA due to publisher restrictions. The published version is available at: https://doi.org/10.1021/ja508631n
Paper 3: H.M. Khan, T. He, E. Fuglebakk, C. Grauffel, B. Yang, M.F. Roberts, A. Gershenson, N. Reuter, “A role for weak electrostatic interactions in peripheral membrane protein binding”, Biophysical Journal, vol. 110(6), pp. 1367-1378, 2016. The article is available at: http://hdl.handle.net/1956/12697
Paper 4: H.M. Khan, C. Grauffel, R. Broer, A.D. MacKerell Jr., R.W.A. Havenith, N. Reuter, “Improving the force field description of tyrosine-choline cation-π interactions: QM investigation of phenol-N(Me)4+ interactions”, Journal of Chemical Theory and Computation, vol. 12, pp. 5585−5595, 2016. The article is not available in BORA due to publisher restrictions. The published version is available at: https://doi.org/10.1021/acs.jctc.6b00654