Fig. 1: Exploring the consequences of geometric target (mis)matching.
a, Large trimeric glycoprotein complexes are characteristic of many human pathogens as exemplified by SARS-CoV-2 spike protein. Figure created in Blender (https://www.blender.org), using PDB 3JCL as a spike model. b, Schematic for Gillespie simulation of multivalent selection against a homotrimeric target. A random library of binding units with varying spatial tolerances for simultaneous target engagement and a set of multimerization scaffolds with increasing interligand spacing were tested. The initial probability density function (PDF) of affinities (top) and linkers (bottom) for the binding unit library is given. c, Simulation results of multivalent selection for libraries prepared with different multivalent scaffolds show that matching scaffold geometry facilitates the selection of assemblies with the highest avidity. All Gillespie simulations were performed in 10 replicates (n = 10); results are shown as average PDFs. d, The PDF of linkers in the binding unit library in the final round of multivalent selection is determined by the scaffold geometry. GM, geometric mean. e, Schematic representation of MEDUSA’s molecular architecture. f, Cryo-EM 3D class-average electron density of a designed MEDUSA. The respective Fourier shell correlation analysis is provided in Supplementary Fig. 4. g, Representative atomic force microscopy image of MEDUSA. Scale bar, 20 nm.
