Multivalent binding and selectivity in molecular targeting, recognition and activation

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• Jure Dobnikar (Chinese Academy of Sciences)
• Wednesday 22 November 2023, 13:00-14:00
• Seminar Room 2, Newton Institute.

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SPL - New statistical physics in living matter: non equilibrium states under adaptive control

A prerequisite for biological processes involving recognition, targeting and activation  is the ability to selectively bind to specific cells or surfaces. An ideal “super-selective” probe exploits multivalent binding between its ligands and target receptors to recognize and exclusively bind to target surfaces. I will present our work on physics of multivalent binding and its application to targeting cells, detecting microbial genome, and activation of immune system response. Specifically, we derived design principles for optimal targeting of multicomponent receptor-covered surfaces [1] and studied selective endocytosis of nanoparticles through cell membranes by engineering the composition of the membrane [2].  We also studied the efficiency of genome detection by binding surface-grafted probes to the genomic DNA [3]. We demonstrate that the sensitivity and selectivity of existing screening methods can be significantly enhanced with multivalent targeting. Finally, we explored activation processes triggering the immune system response with a combination of X-ray scattering, computer simulations, statistical mechanics and in-vitro measurements [4,5]. Our results provide a mechanism of receptor activation in certain autoimmune disorders and suggest suggest that the TLR9 -mediated immune response can be modulated deterministically offering new treatment possibilities. Furthermore, our work highlights that simple physical mechanism combining self-assembly of macromolecular clusters and multivalent binding is governing the emergence of specificity from non-specific electrostatic interactions. References: [1] T. Curk, J. Dobnikar, D. Frenkel, PNAS  114 7210 (2017) [2] T. Curk, et al., Nano Lett. 18 5350 (2018) [3] T. Curk et al., PNAS 117 (16) 8719 (2020) [4] N.W. Schmidt et al., Nature Materials 14 696 (2015) [5] E.Y. Lee et al., ACS Nano 11 (12) 12145 (2017)

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