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A lipophilicity-based energy function for membrane-protein modelling and design

Membrane-protein design is an exciting and increasingly successful research area which has led to landmarks including the design of stable and accurate membrane-integral proteins based on coiled-coil motifs. Design of topologically more complex proteins, such as most receptors, channels, and transpo...

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Autores principales: Weinstein, Jonathan Yaacov, Elazar, Assaf, Fleishman, Sarel Jacob
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736313/
https://www.ncbi.nlm.nih.gov/pubmed/31461441
http://dx.doi.org/10.1371/journal.pcbi.1007318
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author Weinstein, Jonathan Yaacov
Elazar, Assaf
Fleishman, Sarel Jacob
author_facet Weinstein, Jonathan Yaacov
Elazar, Assaf
Fleishman, Sarel Jacob
author_sort Weinstein, Jonathan Yaacov
collection PubMed
description Membrane-protein design is an exciting and increasingly successful research area which has led to landmarks including the design of stable and accurate membrane-integral proteins based on coiled-coil motifs. Design of topologically more complex proteins, such as most receptors, channels, and transporters, however, demands an energy function that balances contributions from intra-protein contacts and protein-membrane interactions. Recent advances in water-soluble all-atom energy functions have increased the accuracy in structure-prediction benchmarks. The plasma membrane, however, imposes different physical constraints on protein solvation. To understand these constraints, we recently developed a high-throughput experimental screen, called dsTβL, and inferred apparent insertion energies for each amino acid at dozens of positions across the bacterial plasma membrane. Here, we express these profiles as lipophilicity energy terms in Rosetta and demonstrate that the new energy function outperforms previous ones in modelling and design benchmarks. Rosetta ab initio simulations starting from an extended chain recapitulate two-thirds of the experimentally determined structures of membrane-spanning homo-oligomers with <2.5Å root-mean-square deviation within the top-predicted five models (available online: http://tmhop.weizmann.ac.il). Furthermore, in two sequence-design benchmarks, the energy function improves discrimination of stabilizing point mutations and recapitulates natural membrane-protein sequences of known structure, thereby recommending this new energy function for membrane-protein modelling and design.
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spelling pubmed-67363132019-09-20 A lipophilicity-based energy function for membrane-protein modelling and design Weinstein, Jonathan Yaacov Elazar, Assaf Fleishman, Sarel Jacob PLoS Comput Biol Research Article Membrane-protein design is an exciting and increasingly successful research area which has led to landmarks including the design of stable and accurate membrane-integral proteins based on coiled-coil motifs. Design of topologically more complex proteins, such as most receptors, channels, and transporters, however, demands an energy function that balances contributions from intra-protein contacts and protein-membrane interactions. Recent advances in water-soluble all-atom energy functions have increased the accuracy in structure-prediction benchmarks. The plasma membrane, however, imposes different physical constraints on protein solvation. To understand these constraints, we recently developed a high-throughput experimental screen, called dsTβL, and inferred apparent insertion energies for each amino acid at dozens of positions across the bacterial plasma membrane. Here, we express these profiles as lipophilicity energy terms in Rosetta and demonstrate that the new energy function outperforms previous ones in modelling and design benchmarks. Rosetta ab initio simulations starting from an extended chain recapitulate two-thirds of the experimentally determined structures of membrane-spanning homo-oligomers with <2.5Å root-mean-square deviation within the top-predicted five models (available online: http://tmhop.weizmann.ac.il). Furthermore, in two sequence-design benchmarks, the energy function improves discrimination of stabilizing point mutations and recapitulates natural membrane-protein sequences of known structure, thereby recommending this new energy function for membrane-protein modelling and design. Public Library of Science 2019-08-28 /pmc/articles/PMC6736313/ /pubmed/31461441 http://dx.doi.org/10.1371/journal.pcbi.1007318 Text en © 2019 Weinstein et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Weinstein, Jonathan Yaacov
Elazar, Assaf
Fleishman, Sarel Jacob
A lipophilicity-based energy function for membrane-protein modelling and design
title A lipophilicity-based energy function for membrane-protein modelling and design
title_full A lipophilicity-based energy function for membrane-protein modelling and design
title_fullStr A lipophilicity-based energy function for membrane-protein modelling and design
title_full_unstemmed A lipophilicity-based energy function for membrane-protein modelling and design
title_short A lipophilicity-based energy function for membrane-protein modelling and design
title_sort lipophilicity-based energy function for membrane-protein modelling and design
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736313/
https://www.ncbi.nlm.nih.gov/pubmed/31461441
http://dx.doi.org/10.1371/journal.pcbi.1007318
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