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Combining experimental NMR residual dipolar couplings, solution X\u2010ray scattering and protein engineering with ensemble simulated annealing, we obtain a quantitative description of the configurational space sampled by the two zinc knuckles, the linker and disordered termini in the absence of nucleic acids. We first compute the conformational ensemble (with an optimal size of three members) of an engineered nucleocapsid construct lacking the N\u2010 and C\u2010termini that satisfies the experimental restraints, and then validate this ensemble, as well as characterize the disordered termini, using the experimental data from the full\u2010length nucleocapsid construct. The experimental and computational strategy is generally applicable to multidomain proteins. Differential flexibility within the linker results in asymmetric motion of the zinc knuckles which may explain their functionally distinct roles despite high sequence identity. One of the configurations (populated at a level of \u224840\u2009%) closely resembles that observed in various ligand\u2010bound forms, providing evidence for conformational selection and a mechanistic link between protein dynamics and function.<\/jats:p>","DOI":"10.1002\/cphc.201600212","type":"journal-article","created":{"date-parts":[[2016,3,6]],"date-time":"2016-03-06T03:27:42Z","timestamp":1457234862000},"page":"1548-1552","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Quantitative Characterization of Configurational Space Sampled by HIV\u20101 Nucleocapsid Using Solution NMR, X\u2010ray Scattering and Protein Engineering"],"prefix":"10.1002","volume":"17","author":[{"given":"Lalit","family":"Deshmukh","sequence":"first","affiliation":[{"name":"Laboratory of Chemical Physics National Institute of Diabetes and Digestive and Kidney Diseases  Bethesda MD 20892-0520 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles D.","family":"Schwieters","sequence":"additional","affiliation":[{"name":"Imaging Sciences Laboratory Center for Information and Technology  Bethesda MD 20892-5624 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Grishaev","sequence":"additional","affiliation":[{"name":"Institute of Bioscience and Biotechnology Research University of Maryland  Rockville MD 20850 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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