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

Autor: Weinstein JY; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel., Elazar A; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel., Fleishman SJ; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
Jazyk: angličtina
Zdroj: PLoS computational biology [PLoS Comput Biol] 2019 Aug 28; Vol. 15 (8), pp. e1007318. Date of Electronic Publication: 2019 Aug 28 (Print Publication: 2019).
DOI: 10.1371/journal.pcbi.1007318
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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