Linked Life Data

19643976

Source:http://linkedlifedata.com/resource/pubmed/id/19643976

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pubmed-article:19643976pubmed:dateCreated2009-8-26lld:pubmed
pubmed-article:19643976pubmed:abstractTextThe success of antibody-based pharmaceuticals has led to a resurgence in interest in computational structure-based design. Most efforts to date have been on the redesign of existing interfaces. These efforts have mostly neglected the inherent flexibility of the receptor that is critical for binding. In this work, we extend on a previous study to perform a series of designs of protein binding interfaces by incorporating receptor flexibility using an ensemble of conformers collected from explicit-solvent molecular dynamics (MD) simulations. All designer complexes are subjected to 30 ns of MD in explicit solvent to assess for stability for a total of 480 ns of dynamics. This is followed by end-point free energy calculations whereby intermolecular potential energy, polar and non-polar solvation energy and entropy of ligand and receptor are subtracted from that of the complex and averaged over 320 snapshots collected from each of the 30 ns MD simulations. Our initial effort consisted of redesigning the interface of three well-studied complexes, namely barnase-barstar, lysozyme-antibody D1.3 and trypsin-BPTI. The design was performed with flexible backbone approach. MD simulations revealed that all three complexes remained stable. Interestingly, the redesigned trypsin-BPTI complex was significantly more favorable than the native complex. This was attributed to the favorable electrostatics and entropy that complemented the already favorable non-polar component. Another aspect of this work consisted of grafting the surface of three proteins, namely tenascin, CheY and MBP1 to bind to barnase, trypsin and lysozyme. The process was initially performed using fixed backbone, and more than 300 ns of the explicit-solvent MD simulation revealed some of the complexes to dissociate over the course of the trajectories, whereas others remained stable. Free energy calculations confirmed that the non-polar component of the free energy as computed by summing the van der Waals energy and the non-polar solvation energy was a strong predictor of stability. Four complexes (two stable and two unstable) were selected, and redesigned using multiple conformers collected from the MD simulation. The resulting designer systems were then immersed in explicit solvent and 30 ns of MD was carried out on each. Interestingly, those complexes that were initially stable remained stable, whereas one of the unstable complexes became stable following redesign with flexible backbone. Free energy calculations showed significant improvements in the affinity for most complexes, revealing that the use of multiple conformers in protein design may significantly enhance such efforts.lld:pubmed
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pubmed-article:19643976pubmed:authorpubmed-author:LiangShideSlld:pubmed
pubmed-article:19643976pubmed:authorpubmed-author:MerouehSamy...lld:pubmed
pubmed-article:19643976pubmed:authorpubmed-author:LiLiweiLlld:pubmed
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pubmed-article:19643976pubmed:pagination575-86lld:pubmed
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pubmed-article:19643976pubmed:year2009lld:pubmed
pubmed-article:19643976pubmed:articleTitleIncorporating receptor flexibility in the molecular design of protein interfaces.lld:pubmed
pubmed-article:19643976pubmed:affiliationDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.lld:pubmed
pubmed-article:19643976pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:19643976pubmed:publicationTypeResearch Support, U.S. Gov't, Non-P.H.S.lld:pubmed
pubmed-article:19643976pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed
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