Enhanced Sampling of Interdomain Motion Using Map-Restrained Langevin Dynamics and NMR: Application to Pin1
| Autor: | Jeffrey W. Peng, David A. Case, Junchao Xia, Jill J. Bouchard |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Conformation Protein domain Motion (geometry) Rigidity (psychology) 010402 general chemistry 01 natural sciences Article Domain (software engineering) 03 medical and health sciences Motion Sampling (signal processing) Protein Domains Structural Biology Humans Langevin dynamics Molecular Biology Conformational ensembles Nuclear Magnetic Resonance Biomolecular Physics Quantitative Biology::Biomolecules Binding Sites Dynamics (mechanics) 0104 chemical sciences NIMA-Interacting Peptidylprolyl Isomerase 030104 developmental biology Mutation Biological system |
| Zdroj: | Journal of molecular biology. 430(14) |
| ISSN: | 1089-8638 |
| Popis: | 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 data. We illustrate this protocol on human Pin1, a two-domain peptidyl-prolyl isomerase relevant for cancer and Alzheimer's disease. The results include the ensemble of domain orientations sampled by Pin1, as well as those of a dysfunctional variant, I28A-Pin1. The differences between the ensembles corroborate our previous spin relaxation results that showed weakened interdomain contact in the I28A variant relative to wild type. Our protocol extends our abilities to explore the functional significance of protein domain motions. |
| Databáze: | OpenAIRE |
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