Enhanced Sampling of Interdomain Motion Using Map-Restrained Langevin Dynamics and NMR: Application to Pin1

Journal of Molecular Biology
Jill J BouchardJeffrey W Peng

Abstract

Many signaling proteins consist of globular domains connected by flexible linkers that allow for substantial domain motion. Because these domains often serve as complementary functional modules, the possibility of functionally important domain motions arises. To explore this possibility, we require knowledge of the ensemble of protein conformations sampled by interdomain motion. Measurements of NMR residual dipolar couplings (RDCs) of backbone HN bonds offer a per-residue characterization of interdomain dynamics, as the couplings are sensitive to domain orientation. A challenge in reaching this potential is the need to interpret the RDCs as averages over dynamic ensembles of domain conformations. Here, we address this challenge by introducing an efficient protocol for generating conformational ensembles appropriate for flexible, multi-domain proteins. The protocol uses map-restrained self-guided Langevin dynamics simulations to promote collective, interdomain motion while restraining the internal domain motion to near rigidity. Critically, the simulations retain an all-atom description for facile inclusion of site-specific NMR RDC restraints. The result is the rapid generation of conformational ensembles consistent with the RDC...Continue Reading

Citations

Dec 22, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Alexandra BornBeat Vögeli
Sep 24, 2020·The Journal of Biological Chemistry·Meiling ZhangJeffrey W Peng
Jan 18, 2021·The Journal of Biological Chemistry·Meiling ZhangJeffrey W Peng
May 6, 2021·Current Opinion in Structural Biology·H Jane Dyson, Peter E Wright
Sep 29, 2021·Journal of the American Chemical Society·Alexandra BornBeat Vögeli

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