2019/08/22 by Suman Saurabh, Francesco Piazza, Saurabh, Suman +1
Engineering · Medicine · Physics and Astronomy · #Biomolecules (q-bio.BM) #FOS: Biological sciences #FOS: Physical sciences #Force Microscopy Techniques and Applications #Molecular Junctions and Nanostructures #Monoclonal and Polyclonal Antibodies Research #Soft Condensed Matter (cond-mat.soft)
paper · pdf · doi:10.48550/arxiv.1908.08309
openalex publication_date 2019/08/22 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
The last decade has witnessed a swiftly increasing interest in the design and\nproduction of novel multivalent molecules as powerful alternatives for\nconventional antibodies in the fight against cancer and infectious diseases.\nHowever, while it is widely accepted that large-scale flexibility (10-100 nm)\nand free/constrained dynamics (100 ns - \μs) control the activity of such\nnovel molecules, computational strategies at the mesoscale still lag behind\nexperiments in optimizing the design of crucial features, such as the binding\ncooperativity (a.k.a. avidity).\n In this study, we introduced different coarse-grained models of a\npolymer-linked, two-nanobody composite molecule, with the aim of laying down\nthe physical bases of a thorough computational drug design protocol at the\nmesoscale. We show that the calculation of suitable potentials of mean force\nallows one to apprehend the nature, range and strength of the thermodynamic\nforces that govern the motion of free and wall-tethered molecules. Furthermore,\nwe develop a simple computational strategy to quantify the\nencounter/dissociation dynamics between the free end of a wall-tethered\nmolecule and the surface, at the roots of binding cooperativity. This procedure\nallows one to pinpoint the role of internal flexibility and weak non-specific\ninteractions on the kinetic constants of the NB-wall encounter and\ndissociation. Finally, we quantify the role and weight of rare events, which\nare expected to play a major role in real-life situations, such as in the\nimmune synapse, where the binding kinetics is likely dominated by fluctuations.\n