title: Transforming binding affinities from three dimensions to two with application to cadherin clustering.
abstract: Membrane-bound receptors often form large assemblies resulting from binding to soluble ligands, cell-surface molecules on other cells and extracellular matrix proteins. For example, the association of membrane proteins with proteins on different cells (trans-interactions) can drive the oligomerization of proteins on the same cell (cis-interactions). A central problem in understanding the molecular basis of such phenomena is that equilibrium constants are generally measured in three-dimensional solution and are thus difficult to relate to the two-dimensional environment of a membrane surface. Here we present a theoretical treatment that converts three-dimensional affinities to two dimensions, accounting directly for the structure and dynamics of the membrane-bound molecules. Using a multiscale simulation approach, we apply the theory to explain the formation of ordered, junction-like clusters by classical cadherin adhesion proteins. The approach features atomic-scale molecular dynamics simulations to determine interdomain flexibility, Monte Carlo simulations of multidomain motion and lattice simulations of junction formation. A finding of general relevance is that changes in interdomain motion on trans-binding have a crucial role in driving the lateral, cis-, clustering of adhesion receptors.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Wu
authors.forename: Jeremie
authors.initials: J
authors.lastname: Vendome
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.forename: Avinoam
authors.initials: A
authors.lastname: Ben-Shaul
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
mesh_terms: D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D019038:Platelet Glycoprotein GPIb-IX Complex; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
chemical_list: D015820:Cadherins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor