Multiscale Simulations of Signalling at Membranes

Abstract

Signalling across, within, and at the cytoplasmic surface of cell membranes is central to the regulation of many processes in mammalian cells, ranging from development and maintenance of tissues to immune responses. Multiscale molecular simulations may be used to probe how signalling proteins interact with the lipid bilayer environment [1] and with one another to form dynamic complexes in cell membranes. The longer term aim of this work is to form a computational bridge from structural across to cell biology to enable predictive modelling of cell membrane signalling. Recent studies on lipid/protein [2], and protein/protein interactions in cell membranes will be described, including studies of PH domain/PIP interactions [3], signalling by integrins [4], and membrane recognition by PTEN and related proteins.[1] Stansfeld, P.J. & Sansom, M.S.P. (2011) From coarse-grained to atomistic: a serial multi-scale approach to membrane protein simulations. J. Chem. Theor. Comp. 7: 1157-1166[2] Stansfeld, P.J., Hopkinson, R., Ashcroft, F.M. & Sansom, M.S.P. (2009) The PIP2 binding site in Kir channels: definition by multi-scale biomolecular simulations. Biochem. 48:10926-10933[3] Lumb, C.N., He, J., Xue, Y., Stansfeld, P.J., Stahelin, R.V., Kutateladze, T.G. & Sansom, M.S.P. (2011) Biophysical and computational studies reveal the extent of membrane penetration of the GRP1 pleckstrin homology domain. Structure 19:1338-1346[4] Kalli, A., Campbell, I.D. & Sansom, M.S.P. (2011) Multiscale simulations suggest a mechanism for integrin inside-out activation. Proc. Natl. Acad. Sci. USA 108:11890-11895.