The Role of the Active Site Flap in Streptavidin/Biotin Complex Formation.
Obtaining a detailed description of how active site flap motion affects substrate or ligand binding will advance structure-based drug design (SBDD) efforts on systems including the kinases, HSP90, HIV protease, ureases, etc. Through this understanding, we will be able to design better inhibitors and...
| Publicado en: | Journal of the American Chemical Society Vol. 140; no. 16; pp. 5434 - 5447 |
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| Autores principales: | , , , , |
| Formato: | Artículo |
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American Chemical Society
4/25/2018
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=hlh&AN=129345631&site=ehost-live header: @attributes: shortDbName: hlh uiTerm: 129345631 longDbName: Humanities International Complete uiTag: AN controlInfo: bkinfo: jinfo: jid: 00027863 ACS jtl: Journal of the American Chemical Society issn: 00027863 maglogo: N pubinfo: dt: 4/25/2018 vid: 140 iid: 16 pid: 997 pub: American Chemical Society artinfo: ui: 129345631 10.1021/jacs.8b00743 ppf: 5434 ppct: 13 formats: tig: atl: The Role of the Active Site Flap in Streptavidin/Biotin Complex Formation. aug: au: Bansal, Nupur Zheng Zheng Lin Frank Song Jun Pei Merz, Jr., Kenneth M. affil: Department of Chemistry and Department of Biochemistry and Molecular Biology, Michigan State University, 578 South Shaw Lane, East Lansing, Michigan 48824, United States Institute for Cyber Enabled Research, Michigan State University, 567 Wilson Road, East Lansing, Michigan 48824, United States su: Streptavidin Biotin Ligand binding (Biochemistry) Proteins Free energy (Thermodynamics) Kinases Urease sug: subj: Streptavidin Biotin Ligand binding (Biochemistry) Proteins Free energy (Thermodynamics) Kinases Urease ab: Obtaining a detailed description of how active site flap motion affects substrate or ligand binding will advance structure-based drug design (SBDD) efforts on systems including the kinases, HSP90, HIV protease, ureases, etc. Through this understanding, we will be able to design better inhibitors and better proteins that have desired functions. Herein we address this issue by generating the relevant configurational states of a protein flap on the molecular energy landscape using an approach we call MT and then following this with a procedure to estimate the free energy associated with the motion of the flap region. To illustrate our overall workflow, we explored the free energy changes in the streptavidin/biotin system upon introducing conformational flexibility in loop in the biotin unbound (apo) and bound (holo) state. The free energy surfaces were created using the Movable Type free energy method, and for further validation, we compared them to potential of mean force (PMF) generated free energy surfaces using MD simulations employing the FF99SBILDN and FF14SB force fields. We also estimated the free energy thermodynamic cycle using an ensemble of closed-like and open-like end states for the ligand unbound and bound states and estimated the binding free energy to be approximately -16.2 kcal/mol (experimental -18.3 kcal/mol). The good agreement between MT in combination with the MT method with experiment and MD simulations supports the effectiveness of our strategy in obtaining unique insights into the motions in proteins that can then be used in a range of biological and biomedical applications. pubtype: Academic Journal doctype: Article src: R language: English refInfo: copyright: @attributes: flag: Y dt: @attributes: year: 2018 holdings: @attributes: islocal: N |
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