Roivant Sciences (United States)

About: Roivant Sciences (United States) is a company organization based out in . It is known for research contribution in the topics: Biology & Chemistry. The organization has 3 authors who have published 10 publications receiving 9 citations.

Modeling the Effect of Cooperativity in Ternary Complex Formation and Targeted Protein Degradation Mediated by Heterobifunctional Degraders

Abstract: Chemically induced proximity between certain endogenous enzymes and a protein of interest (POI) inside cells may cause post-translational modifications to the POI with biological consequences and potential therapeutic effects. Heterobifunctional (HBF) molecules that bind with one functional part to a target POI and with the other to an E3 ligase induce the formation of a target-HBF-E3 ternary complex, which can lead to ubiquitination and proteasomal degradation of the POI. Targeted protein degradation (TPD) by HBFs offers a promising approach to modulate disease-associated proteins, especially those that are intractable using other therapeutic approaches, such as enzymatic inhibition. The three-way interactions among the HBF, the target POI, and the ligase─including the protein–protein interaction between the POI and the ligase─contribute to the stability of the ternary complex, manifested as positive or negative binding cooperativity in its formation. How such cooperativity affects HBF-mediated degradation is an open question. In this work, we develop a pharmacodynamic model that describes the kinetics of the key reactions in the TPD process, and we use this model to investigate the role of cooperativity in the ternary complex formation and in the target POI degradation. Our model establishes the quantitative connection between the ternary complex stability and the degradation efficiency through the former’s effect on the rate of catalytic turnover. We also develop a statistical inference model for determining cooperativity in intracellular ternary complex formation from cellular assay data and demonstrate it by quantifying the change in cooperativity due to site-directed mutagenesis at the POI-ligase interface of the SMARCA2-ACBI1-VHL ternary complex. Our pharmacodynamic model provides a quantitative framework to dissect the complex HBF-mediated TPD process and may inform the rational design of effective HBF degraders.

Characterizing Receptor Flexibility to Predict Mutations That Lead to Human Adaptation of Influenza Hemagglutinin

Abstract: A key step in the emergence of human pandemic influenza strains has been a switch in binding preference of the viral glycoprotein hemagglutinin (HA) from avian to human sialic acid (SA) receptors. The conformation of the bound SA varies substantially with HA sequence, and crystallographic evidence suggests that the bound SA is flexible, making it difficult to predict which mutations are responsible for changing HA-binding preference. We performed molecular dynamics (MD) simulations of SA analogues binding to various HAs and observed a dynamic equilibrium among structurally diverse receptor conformations, including conformations that have not been experimentally observed. Using one such novel conformation, we predicted─and experimentally confirmed─a set of mutations that substantially increased an HA’s affinity for a human SA analogue. This prediction could not have been inferred from the existing crystal structures, suggesting that MD-generated HA–SA conformational ensembles could help researchers predict human-adaptive mutations, aiding surveillance of emerging pandemic threats.

Non-equilibrium protein folding and activation by ATP-driven chaperones

Abstract: A bstract Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein sub-strates in their native structures out of thermal equilibrium. The mechanism of such non-equilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying principle that underlies the conversion of chemical energy from ATP hydrolysis to the conformational free energy associated with protein folding and activation. I demonstrate that non-equilibrium folding requires the chaperones to break at least one of four symmetry conditions. The Hsp70 and Hsp90 chaperones each breaks a different subset of these symmetries and thus they use different mechanisms for non-equilibrium protein folding. I derive an upper bound on the non-equilibrium elevation of the native concentration, which implies that non-equilibrium folding only occurs in slow-folding proteins that adopt an unstable intermediate conformation in binding to ATP-driven chaperones. Contrary to the long-held view of Anfinsen’s hypothesis that proteins fold to their conformational free energy minima, my results predict that some proteins may fold into thermo-dynamically unstable native structures with the assistance of ATP-driven chaperones, and that the native structures of some chaperone-dependent proteins may be shaped by their chaperone-mediated folding pathways.