A self-consistent theory of non-specific and specific interactions of membranes and vesicles with hard, soft polymeric, and fluctuating substrates
Final Report Abstract
Apart from being a source of fascinating physics at reduced dimensionality, fluid membranes, together with the cytoskeleton and the extracellular matrix, are responsible for the structural integrity of living cells. Membranes are part of an edifice that provides the working environment for the smaller, biochemically active, peptides and proteins, thereby determining the spatial coordination for the molecular recognition events. Consequently, biological signalling is subject to a plethora of physical constraints, where the material properties of the structure, as well as active and thermal fluctuations, affect the diffusion and the formation of macromolecular complexes. These effects were the main subject of study within the scope of this proposal entitled “A Self-Consistent Theory of Non-specific and Specific Interactions of Membranes and Vesicles with Hard, Soft Polymeric, and Fluctuating Substrates”. This endeavour synergistically combines theoretical with the experimental developments which emerged in a collaborative effort of several groups centred on a common goal of deepening our understanding of membrane adhesion. Membrane adhesion couples a number of time and length scales, which is a significant challenge for theoretical modelling. Thereby the elements of a process had to be first understood on a particular scale and then appropriately coarse grained. Various techniques and methods including analytical and numerical modelling, as well as simulations were developed to bridge appropriately the relevant scales in a physically consistent manner and to achieve our research goals. Building on our long standing experience in modeling membranes, we developed an analytic theory within which, first, the renormalization of the ligand-receptor affinity emerged due to the confinement of binders to fluctuating membranes. Second, static correlations between two bonds anchoring opposing membranes could be calculated. This theory was important for providing explanation for the structures of adhesion domains observed experimentally. Supported by further experimental efforts, we modeled the force resistance of adhesion domains, observed initially in the mechano-sensing of cells. This work relied on our development of a label-free Dynamic Reflection Interference Microscopy technique to detect objects of sub-optical size, with which we were able to demonstrate the coexistence of sparse and densely packed adhesion domains, as well as jammed structures when the receptors maintain lateral mobility. We gained important insights into the dynamic aspects of the formation of bond clusters by developing a Langevin simulation setup, where the stochastic nature of bond association and dissociation has been explicitly modeled and coupled to the spacio-temporal behavior of the membrane. The gained knowledge was then used to experimentally identify the nucleation events. We were furthermore able to construct an analytic theory for the nucleation of the clusters of bonds. The model is based on a numerically solved master equation with effective rates, and on an analogy with the problem of the first mean passage time. Our model suggests that sparsely distributed bonds in the early stages of nucleation may precede the formation of compact domains at later time scales, which was, in effect experimentally observed. While significant progress in modeling adhesion has been achieved within the scope of the current project as reported, membrane adhesion remains an open challenge. The performed work clarified the emergence of effective affinity, as well as deepened our understanding of the dynamics of reaction limited adhesion. However, the diffusion limited processes and the formation of jammed structures, when both ligands and receptors are mobile, need further theoretical investigation. These processes require effective coarse graining, at least in the time domain. Our work on modeling nucleation will provide an excellent foundation to address these new challenges.
Publications
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Langmuir 2007, 23, 12293-12300. Adhesion of Giant Vesicles Mediated by Weak Binding of Sialyl-LewisX to E-Selectin in the Presence of Repelling Poly(ethylene glycol) Molecules
Lorz, B. G.; Smith, A.-S.; Gege, C. & Sackmann, E.
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Phys. Rev. Lett., 2008, 101, 208103. Dynamics of Specific Vesicle-Substrate Adhesion: From Local Events to Global Dynamics
Reister-Gottfried, E.; Sengupta, K.; Lorz, B.; Sackmann, E.; Seifert, U. & Smith, A.-S.
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Proc. Nat. Acad. Sci. U.S.A., 2008, 105, 6906-6911. Force-induced growth of adhesion domains is controlled by receptor mobility
Smith, A.-S.; Sengupta, K.; Goennenwein, S.; Seifert, U. & Sackmann, E.
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ChemPhysChem, 2009, 10, 66-78. Progress in Mimetic Studies of Cell Adhesion and the Mechanosensing
Smith, A.-S. & Sackmann, E.
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Europhys. Lett., 2010, 89, 28003. Inferring spatial organization of bonds within adhesion clusters by exploiting fluctuations of soft interfaces
Smith, A.-S.; Fenz, S. F. & Sengupta, K.
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Adv. Mater., 2011, 23, 2622-2626. Switching from Ultraweak to Strong Adhesion
Fenz, S. F.; Bihr, T.; Merkel, R.; Seifert, U.; Sengupta, K. & Smith, A.-S.
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New J. Phys., 2011, 13, 025003 Two intertwined facets of adherent membranes: membrane roughness and correlations between ligand-receptors bonds
Reister, E.; Bihr, T.; Seifert, U. & Smith, A.-S.
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Soft Matter, 2011, 7, 952-962. Inter-membrane adhesion mediated by mobile linkers: Effect of receptor shortage
Fenz, S. F.; Smith, A.-S.; Merkel, R. & Sengupta, K.
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EPL, 2012, 99, 38003 Coexistence of dilute and densely packed domains of ligand-receptor bonds in membrane adhesion
Schmidt, D.; Bihr, T.; Seifert, U. & Smith, A.-S.
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Phys. Rev. Lett., 2012, 109, 258101 Nucleation of Ligand-Receptor Domains in Membrane Adhesion
Bihr, T.; Seifert, U. & Smith, A.-S
