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

Elena Papaleo; Carlo Camilloni; Kaare Teilum; Michele Vendruscolo; Kresten Lindorff-Larsen

doi:10.7717/peerj.5125

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

Elena Papaleo, Carlo Camilloni, Kaare Teilum, Michele Vendruscolo, Kresten Lindorff-Larsen^*

^*Corresponding author for this work

Biomolecular Sciences

9 Citations (Scopus)

56 Downloads (Pure)

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 described as having a molten-globule like structure, but with a relatively rigid core. Our approach allowed us to describe the conformational dynamics of NCBD in solution, and to probe the structural heterogeneity resulting from both short- and long-timescale dynamics by the calculation of order parameters on different time scales. These results illustrate the usefulness of our approach since they show thatNCBDis rather rigid on the nanosecond timescale, but interconverts within a broader ensemble on longer timescales, thus enabling the derivation of a coherent set of conclusions from variousNMRexperiments on this protein, which could otherwise appear in contradiction with each other.

Original language	English
Article number	e5125
Journal	PeerJ
Volume	6
Pages (from-to)	1-24
ISSN	2167-8359
DOIs	https://doi.org/10.7717/peerj.5125
Publication status	Published - 2018

Keywords

Ensemble refinement
Force field
Maximum entropy
Molecular dynamics
NMR
Protein dynamics
Protein structure

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Molecular dynamics ensemble refinement of the heterogeneous native state of NCBD using chemical shifts and NOEsFinal published version, 4.98 MBLicence: CC BY

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title = "Molecular dynamics ensemble refinement of the heterogeneous native state of NCBD using chemical shifts and NOEs",

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 described as having a molten-globule like structure, but with a relatively rigid core. Our approach allowed us to describe the conformational dynamics of NCBD in solution, and to probe the structural heterogeneity resulting from both short- and long-timescale dynamics by the calculation of order parameters on different time scales. These results illustrate the usefulness of our approach since they show thatNCBDis rather rigid on the nanosecond timescale, but interconverts within a broader ensemble on longer timescales, thus enabling the derivation of a coherent set of conclusions from variousNMRexperiments on this protein, which could otherwise appear in contradiction with each other.",

keywords = "Ensemble refinement, Force field, Maximum entropy, Molecular dynamics, NMR, Protein dynamics, Protein structure",

author = "Elena Papaleo and Carlo Camilloni and Kaare Teilum and Michele Vendruscolo and Kresten Lindorff-Larsen",

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T1 - Molecular dynamics ensemble refinement of the heterogeneous native state of NCBD using chemical shifts and NOEs

AU - Papaleo, Elena

AU - Camilloni, Carlo

AU - Teilum, Kaare

AU - Vendruscolo, Michele

AU - Lindorff-Larsen, Kresten

PY - 2018

Y1 - 2018

N2 - 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 described as having a molten-globule like structure, but with a relatively rigid core. Our approach allowed us to describe the conformational dynamics of NCBD in solution, and to probe the structural heterogeneity resulting from both short- and long-timescale dynamics by the calculation of order parameters on different time scales. These results illustrate the usefulness of our approach since they show thatNCBDis rather rigid on the nanosecond timescale, but interconverts within a broader ensemble on longer timescales, thus enabling the derivation of a coherent set of conclusions from variousNMRexperiments on this protein, which could otherwise appear in contradiction with each other.

AB - 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 described as having a molten-globule like structure, but with a relatively rigid core. Our approach allowed us to describe the conformational dynamics of NCBD in solution, and to probe the structural heterogeneity resulting from both short- and long-timescale dynamics by the calculation of order parameters on different time scales. These results illustrate the usefulness of our approach since they show thatNCBDis rather rigid on the nanosecond timescale, but interconverts within a broader ensemble on longer timescales, thus enabling the derivation of a coherent set of conclusions from variousNMRexperiments on this protein, which could otherwise appear in contradiction with each other.

KW - Ensemble refinement

KW - Force field

KW - Maximum entropy

KW - Molecular dynamics

KW - NMR

KW - Protein dynamics

KW - Protein structure

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DO - 10.7717/peerj.5125

M3 - Journal article

C2 - 30013831

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SN - 2167-8359

VL - 6

SP - 1

EP - 24

JO - PeerJ

JF - PeerJ

M1 - e5125

ER -

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

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Keywords

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