Rxivist logo

Computational design of highly signaling active membrane receptors through de novo solvent-mediated allosteric networks

By Michael Chen, Jason Lai, Jing Wang, Kris Conners, Anna Russell, Erik Hembre, Marc Rutter, Bradley Condon, Lalitha Kodandapani, Betty Chau, Xun Zhao, Jordi Benach, Kent Baker, Patrick Barth

Posted 01 Oct 2021
bioRxiv DOI: 10.1101/2021.09.29.462228

Protein catalysis and allostery require the atomic-level orchestration and motion of residues, ligand, solvent and protein effector molecules, but the ability to design protein activity through precise protein-solvent cooperative interactions has not been demonstrated. Here, we report the design of a dozen novel membrane receptors catalyzing G-protein nucleotide exchange through diverse de novo engineered allosteric pathways mediated by cooperative networks of intra-protein, protein-ligand and solvent molecule interactions. Consistent with the predictions, designed protein activities strongly correlated with the level of solvent-mediated interaction network plasticity at flexible transmembrane helical interfaces. Several designs displayed considerably enhanced thermostability and activity compared to related natural receptors. The most stable and active variant crystallized in an unforeseen signaling active conformation, in excellent agreement with the design models. The allosteric network topologies of the best designs bear limited similarity to those of natural receptors and reveal a space of allosteric interactions larger than previously inferred from natural proteins. The approach should prove useful for engineering proteins with novel complex protein catalytic and signaling activities.

Download data

  • Downloaded 293 times
  • Download rankings, all-time:
    • Site-wide: 156,299
    • In biophysics: 5,960
  • Year to date:
    • Site-wide: 58,558
  • Since beginning of last month:
    • Site-wide: 113,804

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide