Protein-Ligand Binding


Binding of ligands to proteins is a challenging area for coarse-grained models. Most binding pockets require specific hydrogen bonding patterns and a neat fit of the ligand. With a CG model such as Martini that lacks directional hydrogen bonds and can not represent the fine details of the packing, ligand binding may require multi-scale methods.

However, less specific binding may be modeled with Martini, and more and more examples are appearing in the literature. Mostly they concern the binding of lipids to membrane proteins [2-14] or membrane-bound antimicrobial peptides [15]. The figure shows an example of binding of poly-unsaturated lipids to a trans-membrane peptide in a multi-component membrane [2].

Until now, there is only one example of a Martini study on ligand binding to a soluble protein: the binding of a peptide to the OppA transport receptor [1].


[1] R.P.A. Berntsson, M.K. Doeven, F. Fusetti, R.H. Duurkens, D. Sengupta, S.J. Marrink, A.M.W.H. Thunnissen, B. Poolman, D.J. Slotboom. The structural basis for peptide selection by the transport receptor OppA. EMBO J., 28:1332-1340, 2009. open access

[2] 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

[3] J. Domanski, S.J. Marrink, L.V. Schaefer. Transmembrane helices can induce domain formation in crowded model biomembranes. BBA Biomembr., 1818:984-994, 2012. abstract

[4] D.H. de Jong, C.A. Lopez, S.J. Marrink. Molecular view on protein sorting into liquid-ordered membrane domains mediated by gangliosides and lipid anchors. Farad. Discuss., accepted. DOI:10.1039/C2FD20086D

[5] G. van den Bogaart, K. Meyenberg, H.J. Risselada, et al., R. Jahn. Membrane protein sequestering by ionic protein–lipid interactions. Nature, 2011. doi:10.1038/nature10545

[6] D. Sengupta, A. Chattopadhyay.Identification of Cholesterol Binding Sites in the Serotonin1A Receptor. J. Phys. Chem. B., Articles ASAP, 2012. DOI: 10.1021/jp309888u

[7] A. Koivuniemi, T. Vuorela, P.T. Kovanen, I. Vattulainen, M.T. Hyvönen. Lipid Exchange Mechanism of the Cholesteryl Ester Transfer Protein Clarified by Atomistic and Coarse-grained Simulations. PLoS Comp. Biol., 2012, doi:10.1371/journal.pcbi.1002299

[8] F. Yin, J.T. Kindt. Hydrophobic Mismatch and Lipid Sorting Near OmpA in Mixed Bilayers: Atomistic and Coarse-Grained Simulations. Biophys. J. 102:2279-2287, 2012.

[9] J. Karo, P. Peterson, M. Vendelin. Molecular Dynamics Simulations of Creatine Kinase and Adenine Nucleotide Translocase in Mitochondrial Membrane Patch. J. Biol. Chem. 287:7467-7476, 2012.

[10] A. Hung, I. Yarovsky. Gap Junction Hemichannel Interactions with Zwitterionic Lipid, Anionic Lipid, and Cholesterol: Molecular Simulation Studies. Biochem. 50: 1492-1504, 2011. 

[11] C.N. Lumb, M.S.P. Sansom, Finding a Needle in a Haystack: The Role of Electrostatics in Target Lipid Recognition by PH Domains. PLoS Comp. Biol.  8:e1002617, 2012.

[12] P.J. Stansfeld, R. Hopkinson, F.M. Ashcroft, M.S.P. Sansom. PIP2-Binding Site in Kir Channels: Definition by Multiscale Biomolecular Simulations. Biochem. 48:10926-10933, 2009.

[13] H. Koldsø, M.S.P. Sansom. Local Lipid Reorganization by a Transmembrane Protein Domain. J. Phys. Chem. Lett., Just Accepted Manuscript, 2012.

[14] M.R. Schmidt, P.J. Stansfeld, S.J. Tucker, M.S.P. Sansom. Simulation-Based Prediction of Phosphatidylinositol 4,5-Bisphosphate Binding to an Ion Channel. Biochemistry, ASAP 2012. DOI: 10.1021/bi301350s 

[15] A.A. Polyansky, R. Ramaswarny, P.E. Volynsky, I.F. Sbalzarini, S.J. Marrink, R.G. Efremov. Antimicrobial peptides induce growth of phosphatidylglycerol domains in a model bacterial membrane. J. Phys. Chem. Letters, 1:3108–3111, 2010. abstract