| Autor: |
Cofas-Vargas LF; Biosystems and Soft Matter Division, Institute of Fundamental Technological Research, Polish Academy of Sciences, ul. Pawińskiego 5B, 02-106 Warsaw, Poland. fcofas@ippt.pan.pl., Olivos-Ramirez GE; Biosystems and Soft Matter Division, Institute of Fundamental Technological Research, Polish Academy of Sciences, ul. Pawińskiego 5B, 02-106 Warsaw, Poland. fcofas@ippt.pan.pl., Chwastyk M; Institute of Physics, Polish Academy of Sciences, al. Lotników 32/46, 02-668 Warsaw, Poland., Moreira RA; NEIKER, Basque Research and Technology Alliance (BRTA), Parque Científico y Tecnológico de Bizkaia, P812, E-48160 Derio, Spain., Baker JL; Department of Chemistry, The College of New Jersey, 2000 Pennington Road, Ewing, NJ 08628, USA., Marrink SJ; Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands. s.j.marrink@rug.nl., Poma AB; Biosystems and Soft Matter Division, Institute of Fundamental Technological Research, Polish Academy of Sciences, ul. Pawińskiego 5B, 02-106 Warsaw, Poland. fcofas@ippt.pan.pl. |
| Abstrakt: |
Rational design of novel antibody therapeutics against viral infections such as coronavirus relies on surface complementarity and high affinity for their effectiveness. Here, we explore an additional property of protein complexes, the intrinsic mechanical stability, in SARS-CoV-2 variants when complexed with a potent antibody. In this study, we utilized a recent implementation of the GōMartini 3 approach to investigate large conformational changes in protein complexes with a focus on the mechanostability of the receptor-binding domain (RBD) from WT, Alpha, Delta, and XBB.1.5 variants in complex with the H11-H4 nanobody. The analysis revealed moderate differences in mechanical stability among these variants. Also, we identified crucial residues in both the RBD and certain protein segments in the nanobody that contribute to this property. By performing pulling simulations and monitoring the presence of specific native and non-native contacts across the protein complex interface, we provided mechanistic insights into the dissociation process. Force-displacement profiles indicate a tensile force clamp mechanism associated with the type of protein complex. Our computational approach not only highlights the key mechanostable interactions that are necessary to maintain overall stability, but it also paves the way for the rational design of potent antibodies that are mechanostable and effective against emergent SARS-CoV-2 variants. |
