Molecular dynamics ensemble refinement of the heterogeneous native state of NCBD using chemical shifts and NOEs

PeerJ
Elena PapaleoKresten Lindorff-Larsen

Abstract

Many proteins display complex dynamical properties that are often intimately linked to their biological functions. As the native state of a protein is best described as an ensemble of conformations, it is important to be able to generate models of native state ensembles with high accuracy. Due to limitations in sampling efficiency and force field accuracy it is, however, challenging to obtain accurate ensembles of protein conformations by the use of molecular simulations alone. Here we show that dynamic ensemble refinement, which combines an accurate atomistic force field with commonly available nuclear magnetic resonance (NMR) chemical shifts and NOEs, can provide a detailed and accurate description of the conformational ensemble of the native state of a highly dynamic protein. As both NOEs and chemical shifts are averaged on timescales up to milliseconds, the resulting ensembles reflect the structural heterogeneity that goes beyond that probed, e.g., by NMR relaxation order parameters. We selected the small protein domain NCBD as object of our study since this protein, which has been characterized experimentally in substantial detail, displays a rich and complex dynamical behaviour. In particular, the protein has been describ...Continue Reading

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Citations

May 30, 2019·The Journal of Membrane Biology·Rajeswari AppaduraiAnand Srivastava
Jun 27, 2020·Frontiers in Cell and Developmental Biology·Valentina SoraElena Papaleo
Aug 30, 2020·International Journal of Molecular Sciences·Joao V de SouzaAgnieszka K Bronowska
Dec 29, 2020·The Journal of Biological Chemistry·Katrine BuggeKaren Skriver
Jan 1, 2021·The Journal of Physical Chemistry. B·Srinivasa M GopalLars V Schäfer
Apr 14, 2021·The Journal of Physical Chemistry. B·Valentina SoraElena Papaleo
Jul 16, 2021·Frontiers in Molecular Biosciences·Matteo LambrughiElena Papaleo
Dec 25, 2019·Journal of Chemical Information and Modeling·Sumudu P Leelananda, Steffen Lindert

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Methods Mentioned

BETA
NMR
X-ray

Software Mentioned

Gromacs
CHARMM
PPM
CRYSOL
Modeller
Plumed
THESEUS
CH3Shift
ENCORE
CHARMM22

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