Simulating Protein Self-Assembly

 

rho_agg3Many integral membrane proteins assemble to form oligomeric structures in biological membranes. The MARTINI force field makes it possible to study these self-assembly processes at near-atomic detail over time scales of micro- to milli-seconds.

The picture shows an example of the aggregation of membrane-embedded rhodopsins into higher order oligomers [1]. Starting from random initial positions, the proteins are observed to form linear aggregates due to a competition of non-specific lipid mediated forces and specific sidechain-sidechain interactions at the protein surface.

Other examples of protein-protein self-assembly simulated with MARTINI include the dimerization of glycophorin A [2], the repressor of primer (ROP) protein [3], the c0-subunit of the ATP synthase complex [4], transmembrane WALP peptides [5,6], and  the transmembrane domain of integrin [7]. In addition to membrane protein self-assembly, aggregation of soluble proteins into nano-fibres [10] has been studied using the Martini model.

The fast sampling speed of Martini also allows computation of the dimerization free energy of membrane proteins; recent studies for GPCR [8,9] and OmpF [11] reveal favorable association interfaces.

[1] X. Periole, T. Huber, S.J. Marrink, T. P. Sakmar. G protein-coupled receptors self-assemble in dynamics simulations of model bilayers. JACS, 129:10126-10132, 2007.

[2] D. Sengupta, S.J. Marrink. Lipid mediated Interactions tune the association of Glycophorin A helix and its disruptive mutants in membranes. Phys. Chem. Chem. Phys., 12:12987-12996, 2010. abstract

[3] X. Periole, M. Cavalli, S.J. Marrink, M. Ceruso. Combining an elastic network with a coarse-grained molecular force field: structure, dynamics and intermolecular recognition. J. Chem. Th. Comp., 5:2531-2543, 2009.

[4] D. Sengupta, A. Rampioni, S.J. Marrink. Simulations of the C-subunit of ATP-synthase reveal helix rearrangements. Mol. Membr. Biol., 26:422-434, 2009.

[5] L.V. Schafer, D.H. de Jong, A. Holt, A.J. Rzepiela, A.H. de Vries, B. Poolman, J.A. Killian, S.J. Marrink. Lipid packing drives the segregation of transmembrane helices into disordered lipid domains in model biomembranes. PNAS, 108:1343-1348, 2011. open access

[6] J. Domanski, S.J. Marrink, L.V. Schaefer. Transmembrane helices can induce domain formation in crowded model biomembranes. BBA Biomembr., in press, 2011. DOI:10.1016/j.bbamem.2011.08.021. abstract

[7] C.P. Chng, S.M. Tan. Leukocyte integrin αLβ2 transmembrane association dynamics revealed by coarse-grained molecular dynamics simulations. Proteins, 79:2203–2213, 2011.

[8] X. Periole, A.M. Knepp, T.P. Sakmar, S.J. Marrink, T. Huber. Structural determinants of the supra-molecular organization of G protein-coupled receptors in bilayers. JACS, 134:10959–10965, 2012. abstract

[9] J.M. Johnston, H. Wang, D. Provasi, M. Filizola. Assessing the relative stability of dimer interfaces in G protein-coupled receptors. PLoS Comput Biol 8: e1002649, 2012.

[10] Y. Komatsu, M. Fukuda, H. Yamada, S. Kawamoto, T. Miyakawa, R. Morikawa, M. Takasu, S. Yokojima, S. Akanuma, A. Yamagishi. Constructing protein nano-fiber and estimation of the electronic state around metal ions. Int. J. Quant. Chem. 112:3750–3755, 2012.

[11] I. Casuso, J. Khao, M. Chami, P. Paul-Gilloteaux, M. Husain, J.P. Duneau, H. Stahlberg, J.N. Sturgis, S. Scheuring. Characterization of the motion of membrane proteins using high-speed atomic force microscopy. Nat. Nanotechnology, in press, 2012. DOI: 10.1038/NNANO.2012.109.