LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins

TB Ansell; W Song; CE Coupland; L Carrique; RA Corey; AL Duncan; CK Cassidy; MMG Geurts; Tim Rasmussen; Andriw Ward; C Siebold; PJ Stansfeld; Mark S P Sansom

doi:10.1038/s41467-023-43392-y

LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins

TB Ansell, W Song, CE Coupland, L Carrique, RA Corey, AL Duncan, CK Cassidy, MMG Geurts, Tim Rasmussen, Andriw Ward, C Siebold, PJ Stansfeld, Mark S P Sansom

School of Physiology, Pharmacology & Neuroscience

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Abstract

Cryo-electron microscopy (cryo-EM) enables the determination of membrane protein structures in native-like environments. Characterising how membrane proteins interact with the surrounding membrane lipid environment is assisted by resolution of lipid-like densities visible in cryo-EM maps. Nevertheless, establishing the molecular identity of putative lipid and/or detergent densities remains challenging. Here we present LipIDens, a pipeline for molecular dynamics (MD) simulation-assisted interpretation of lipid and lipid-like densities in cryo-EM structures. The pipeline integrates the implementation and analysis of multi-scale MD simulations for identification, ranking and refinement of lipid binding poses which superpose onto cryo-EM map densities. Thus, LipIDens enables direct integration of experimental and computational structural approaches to facilitate the interpretation of lipid-like cryo-EM densities and to reveal the molecular identities of protein-lipid interactions within a bilayer environment. We demonstrate this by application of our open-source LipIDens code to ten diverse membrane protein structures which exhibit lipid-like densities.

Original language	English
Article number	7774
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-43392-y
Publication status	Published - 27 Nov 2023

Bibliographical note

Funding Information:
We thank Dr Zachary Berndsen for helpful discussion when preparing the manuscript. The LipIDens logo was designed by Jessica Ansell. T.B.A C.E.C. and M.M.G.G. are supported by Wellcome (102164/Z/13/Z). W.S. acknowledges support from the Newton International Fellowship. R.A.C., A.L.D. M.S.P.S. and P.J.S. are funded by Wellcome (208361/Z/17/Z). A.L.D. has been additionally supported by BBSRC (BB/R00126X/1) and the Department of Biochemistry. C.K.C. is funded by the BBSRC (BB/S003339/1). P.J.S.’s laboratory is also supported by the BBSRC (BB/P01948X/1, BB/R002517/1, and BB/S003339/1), and the MRC (MR/S009213/1) and M.S.P.S.’s research is further supported by the BBSRC (BB/R00126X/1) and PRACE (Partnership for Advanced Computing in Europe, 2016163984). C.S. is supported by Cancer Research UK (C20724/A26752 and DRCRPG-May23/100002), the BBSRC (BB/T01508X/1) and the European Research Council (647278). L.C. is supported by a Wellcome administrative support grant (203141/Z/16/Z). A.B.W. acknowledges support from the Ray Thomas Edwards Foundation. We thank Dr Irfan Alibay and Michael Horrell for the maintenance of local compute resources.

Publisher Copyright:
© 2023, The Author(s).

Keywords

membrane protein
Molecular dynamic simulations

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Ansell, TB., Song, W., Coupland, CE., Carrique, L., Corey, RA., Duncan, AL., Cassidy, CK., Geurts, MMG., Rasmussen, T., Ward, A., Siebold, C., Stansfeld, PJ., & Sansom, M. S. P. (2023). LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins. Nature Communications, 14(1), Article 7774. https://doi.org/10.1038/s41467-023-43392-y

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abstract = "Cryo-electron microscopy (cryo-EM) enables the determination of membrane protein structures in native-like environments. Characterising how membrane proteins interact with the surrounding membrane lipid environment is assisted by resolution of lipid-like densities visible in cryo-EM maps. Nevertheless, establishing the molecular identity of putative lipid and/or detergent densities remains challenging. Here we present LipIDens, a pipeline for molecular dynamics (MD) simulation-assisted interpretation of lipid and lipid-like densities in cryo-EM structures. The pipeline integrates the implementation and analysis of multi-scale MD simulations for identification, ranking and refinement of lipid binding poses which superpose onto cryo-EM map densities. Thus, LipIDens enables direct integration of experimental and computational structural approaches to facilitate the interpretation of lipid-like cryo-EM densities and to reveal the molecular identities of protein-lipid interactions within a bilayer environment. We demonstrate this by application of our open-source LipIDens code to ten diverse membrane protein structures which exhibit lipid-like densities.",

keywords = "membrane protein, Molecular dynamic simulations",

author = "TB Ansell and W Song and CE Coupland and L Carrique and RA Corey and AL Duncan and CK Cassidy and MMG Geurts and Tim Rasmussen and Andriw Ward and C Siebold and PJ Stansfeld and Sansom, {Mark S P}",

note = "Funding Information: We thank Dr Zachary Berndsen for helpful discussion when preparing the manuscript. The LipIDens logo was designed by Jessica Ansell. T.B.A C.E.C. and M.M.G.G. are supported by Wellcome (102164/Z/13/Z). W.S. acknowledges support from the Newton International Fellowship. R.A.C., A.L.D. M.S.P.S. and P.J.S. are funded by Wellcome (208361/Z/17/Z). A.L.D. has been additionally supported by BBSRC (BB/R00126X/1) and the Department of Biochemistry. C.K.C. is funded by the BBSRC (BB/S003339/1). P.J.S.{\textquoteright}s laboratory is also supported by the BBSRC (BB/P01948X/1, BB/R002517/1, and BB/S003339/1), and the MRC (MR/S009213/1) and M.S.P.S.{\textquoteright}s research is further supported by the BBSRC (BB/R00126X/1) and PRACE (Partnership for Advanced Computing in Europe, 2016163984). C.S. is supported by Cancer Research UK (C20724/A26752 and DRCRPG-May23/100002), the BBSRC (BB/T01508X/1) and the European Research Council (647278). L.C. is supported by a Wellcome administrative support grant (203141/Z/16/Z). A.B.W. acknowledges support from the Ray Thomas Edwards Foundation. We thank Dr Irfan Alibay and Michael Horrell for the maintenance of local compute resources. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = nov,

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doi = "10.1038/s41467-023-43392-y",

language = "English",

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TY - JOUR

T1 - LipIDens

T2 - simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins

AU - Ansell, TB

AU - Song, W

AU - Coupland, CE

AU - Carrique, L

AU - Corey, RA

AU - Duncan, AL

AU - Cassidy, CK

AU - Geurts, MMG

AU - Rasmussen, Tim

AU - Ward, Andriw

AU - Siebold, C

AU - Stansfeld, PJ

AU - Sansom, Mark S P

N1 - Funding Information: We thank Dr Zachary Berndsen for helpful discussion when preparing the manuscript. The LipIDens logo was designed by Jessica Ansell. T.B.A C.E.C. and M.M.G.G. are supported by Wellcome (102164/Z/13/Z). W.S. acknowledges support from the Newton International Fellowship. R.A.C., A.L.D. M.S.P.S. and P.J.S. are funded by Wellcome (208361/Z/17/Z). A.L.D. has been additionally supported by BBSRC (BB/R00126X/1) and the Department of Biochemistry. C.K.C. is funded by the BBSRC (BB/S003339/1). P.J.S.’s laboratory is also supported by the BBSRC (BB/P01948X/1, BB/R002517/1, and BB/S003339/1), and the MRC (MR/S009213/1) and M.S.P.S.’s research is further supported by the BBSRC (BB/R00126X/1) and PRACE (Partnership for Advanced Computing in Europe, 2016163984). C.S. is supported by Cancer Research UK (C20724/A26752 and DRCRPG-May23/100002), the BBSRC (BB/T01508X/1) and the European Research Council (647278). L.C. is supported by a Wellcome administrative support grant (203141/Z/16/Z). A.B.W. acknowledges support from the Ray Thomas Edwards Foundation. We thank Dr Irfan Alibay and Michael Horrell for the maintenance of local compute resources. Publisher Copyright: © 2023, The Author(s).

PY - 2023/11/27

Y1 - 2023/11/27

N2 - Cryo-electron microscopy (cryo-EM) enables the determination of membrane protein structures in native-like environments. Characterising how membrane proteins interact with the surrounding membrane lipid environment is assisted by resolution of lipid-like densities visible in cryo-EM maps. Nevertheless, establishing the molecular identity of putative lipid and/or detergent densities remains challenging. Here we present LipIDens, a pipeline for molecular dynamics (MD) simulation-assisted interpretation of lipid and lipid-like densities in cryo-EM structures. The pipeline integrates the implementation and analysis of multi-scale MD simulations for identification, ranking and refinement of lipid binding poses which superpose onto cryo-EM map densities. Thus, LipIDens enables direct integration of experimental and computational structural approaches to facilitate the interpretation of lipid-like cryo-EM densities and to reveal the molecular identities of protein-lipid interactions within a bilayer environment. We demonstrate this by application of our open-source LipIDens code to ten diverse membrane protein structures which exhibit lipid-like densities.

AB - Cryo-electron microscopy (cryo-EM) enables the determination of membrane protein structures in native-like environments. Characterising how membrane proteins interact with the surrounding membrane lipid environment is assisted by resolution of lipid-like densities visible in cryo-EM maps. Nevertheless, establishing the molecular identity of putative lipid and/or detergent densities remains challenging. Here we present LipIDens, a pipeline for molecular dynamics (MD) simulation-assisted interpretation of lipid and lipid-like densities in cryo-EM structures. The pipeline integrates the implementation and analysis of multi-scale MD simulations for identification, ranking and refinement of lipid binding poses which superpose onto cryo-EM map densities. Thus, LipIDens enables direct integration of experimental and computational structural approaches to facilitate the interpretation of lipid-like cryo-EM densities and to reveal the molecular identities of protein-lipid interactions within a bilayer environment. We demonstrate this by application of our open-source LipIDens code to ten diverse membrane protein structures which exhibit lipid-like densities.

KW - membrane protein

KW - Molecular dynamic simulations

UR - http://europepmc.org/abstract/med/38012131

U2 - 10.1038/s41467-023-43392-y

DO - 10.1038/s41467-023-43392-y

M3 - Article (Academic Journal)

C2 - 38012131

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7774

ER -

LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins

Abstract

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Keywords

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