Mapping Protein Conformational Energy Landscapes Using NMR and Molecular Simulation

Guerry, Paul; Mollica, Luca; Blackledge, Martin

doi:10.1002/cphc.201300377

Cited by 13 publications

(13 citation statements)

References 139 publications

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“…It is well-known from solution NMR studies that isotropic chemical shifts are modulated by dynamics, 17 and MD simulations in conjunction with empirical ShiftX-based calculations were reported to explain the dynamic averaging of δ iso in RNaseH. 18 Here, for CA assemblies, large variation in 15 N, 13 C α , and 13 C o δ iso is seen for the different residues, and the extent of variability is generally greater for the loop vs the helical regions of CA (Figure S2, Supporting Information).…”

mentioning

confidence: 99%

HIV-1 Capsid Function Is Regulated by Dynamics: Quantitative Atomic-Resolution Insights by Integrating Magic-Angle-Spinning NMR, QM/MM, and MD

Zhang

Hou

et al. 2016

J. Am. Chem. Soc.

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HIV-1 CA capsid protein possesses intrinsic conformational flexibility, which is essential for its assembly into conical capsids and interactions with host factors. CA is dynamic in the assembled capsid, and residues in functionally important regions of the protein undergo motions spanning many decades of timescales. Chemical shift anisotropy (CSA) tensors, recorded in magic-angle-spinning NMR experiments, provide direct residue-specific probes of motions on nano- to microsecond timescales. We combined NMR, MD, and Density-Functional-Theory calculations, to gain quantitative understanding of internal backbone dynamics in CA assemblies, and found that the dynamically averaged 15N CSA tensors calculated by this joined protocol are in remarkable agreement with experiment. Thus, quantitative atomic-level understanding of the relationships between CSA tensors, local backbone structure and motions in CA assemblies is achieved, demonstrating the power of integrating NMR experimental data and theory for characterizing atomic-resolution dynamics in biological systems.

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mentioning

confidence: 99%

HIV-1 Capsid Function Is Regulated by Dynamics: Quantitative Atomic-Resolution Insights by Integrating Magic-Angle-Spinning NMR, QM/MM, and MD

Zhang

Hou

et al. 2016

J. Am. Chem. Soc.

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“…Other software packages have been developed in recent years specifically for structure calculation of macromolecules from RDC data 16,24,[34][35][36][37][38] . In addition, other analyses have been introduced to perform conformational sampling of dynamical proteins from RDC data 10,[38][39][40][41][42][43][44][45][46] . Here we present a combination of REDCRAFT 12,16,47 and new analysis of its results to explore and assemble conformational states of a dynamical protein.…”

Section: /42mentioning

confidence: 99%

Structure Calculation and Reconstruction of Discrete-State Dynamics from Residual Dipolar Couplings

Cole

Mukhopadhyay

Omar

et al. 2016

J. Chem. Theory Comput.

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Residual dipolar couplings (RDCs) acquired by nuclear magnetic resonance (NMR) spectroscopy are an indispensable source of information in investigation of molecular structures and dynamics. Here, we present a comprehensive strategy for structure calculation and reconstruction of discrete-state dynamics from RDC data that is based on the singular value decomposition (SVD) method of order tensor estimation. In addition to structure determination, we provide a mechanism of producing an ensemble of conformations for the dynamical regions of a protein from RDC data. The developed methodology has been tested on simulated RDC data with ±1 Hz of error from an 83 residue α protein (PDB ID 1A1Z ) and a 213 residue α/β protein DGCR8 (PDB ID 2YT4 ). In nearly all instances, our method reproduced the structure of the protein including the conformational ensemble to within less than 2 Å. On the basis of our investigations, arc motions with more than 30° of rotation are identified as internal dynamics and are reconstructed with sufficient accuracy. Furthermore, states with relative occupancies above 20% are consistently recognized and reconstructed successfully. Arc motions with a magnitude of 15° or relative occupancy of less than 10% are consistently unrecognizable as dynamical regions within the context of ±1 Hz of error.

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“…Enhanced sampling is particularly important when using NMR RDCs and SAXS data, which have timescale sensitivities that generally exceed those accessible by conventional MD simulations. These approaches include Accelerated Molecular Dynamics (AMD)(99; 100), in which the rates of transition between distinct conformational sub-states is increased by adding a continuous non-negative bias potential to the energy surface, that can be used alone or as a relevant conformational pool for a SAS protocol (see below)(101) and NMR-guided metadynamics, which accelerates conformational sampling using collective variable, including chemical shift reproduction(102). …”

Section: Ensemble Determinationmentioning

confidence: 99%

Advances in the Determination of Nucleic Acid Conformational Ensembles

Salmon

Shan

Al‐Hashimi

2014

Annu. Rev. Phys. Chem.

100

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Conformational changes in nucleic acids play a key role in the way genetic information is stored, transferred, and processed in living cells. Here, we describe new approaches that employ a broad range of experimental data, including NMR derived chemical shifts and residual dipolar couplings, small angle X-ray scattering, and computational approaches such as molecular dynamics simulations, to determine ensembles of DNA and RNA at atomic resolution. We review the complimentary information that can be obtained from diverse sets of data and the various methods that have been developed to combine these data with computational methods to construct ensembles and assess their uncertainty. We conclude by surveying RNA and DNA ensembles determined using these methods, highlighting the unique physical and functional insights that have been obtained so far.

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Mapping Protein Conformational Energy Landscapes Using NMR and Molecular Simulation

Cited by 13 publications

References 139 publications

HIV-1 Capsid Function Is Regulated by Dynamics: Quantitative Atomic-Resolution Insights by Integrating Magic-Angle-Spinning NMR, QM/MM, and MD

HIV-1 Capsid Function Is Regulated by Dynamics: Quantitative Atomic-Resolution Insights by Integrating Magic-Angle-Spinning NMR, QM/MM, and MD

Structure Calculation and Reconstruction of Discrete-State Dynamics from Residual Dipolar Couplings

Advances in the Determination of Nucleic Acid Conformational Ensembles

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