Identifying binding hot spots on protein surfaces by mixed‐solvent molecular dynamics: HIV‐1 protease as a test case
dc.contributor.author | Ung, Peter M. U. | en_US |
dc.contributor.author | Ghanakota, Phani | en_US |
dc.contributor.author | Graham, Sarah E. | en_US |
dc.contributor.author | Lexa, Katrina W. | en_US |
dc.contributor.author | Carlson, Heather A. | en_US |
dc.date.accessioned | 2015-11-12T21:04:50Z | |
dc.date.available | 2017-03-01T14:41:59Z | en |
dc.date.issued | 2016-01 | en_US |
dc.identifier.citation | Ung, Peter M. U.; Ghanakota, Phani; Graham, Sarah E.; Lexa, Katrina W.; Carlson, Heather A. (2016). "Identifying binding hot spots on protein surfaces by mixed‐solvent molecular dynamics: HIV‐1 protease as a test case." Biopolymers 105(1): 21-34. | en_US |
dc.identifier.issn | 0006-3525 | en_US |
dc.identifier.issn | 1097-0282 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/116011 | |
dc.description.abstract | Mixed‐solvent molecular dynamics (MixMD) simulations use full protein flexibility and competition between water and small organic probes to achieve accurate hot‐spot mapping on protein surfaces. In this study, we improved MixMD using human immunodeficiency virus type‐1 protease (HIVp) as the test case. We used three probe–water solutions (acetonitrile–water, isopropanol–water, and pyrimidine–water), first at 50% w/w concentration and later at 5% v/v. Paradoxically, better mapping was achieved by using fewer probes; 5% simulations gave a superior signal‐to‐noise ratio and far fewer spurious hot spots than 50% MixMD. Furthermore, very intense and well‐defined probe occupancies were observed in the catalytic site and potential allosteric sites that have been confirmed experimentally. The Eye site, an allosteric site underneath the flap of HIVp, has been confirmed by the presence of a 5‐nitroindole fragment in a crystal structure. MixMD also mapped two additional hot spots: the Exo site (between the Gly16‐Gly17 and Cys67‐Gly68 loops) and the Face site (between Glu21‐Ala22 and Val84‐Ile85 loops). The Exo site was observed to overlap with crystallographic additives such as acetate and dimethyl sulfoxide that are present in different crystal forms of the protein. Analysis of crystal structures of HIVp in different symmetry groups has shown that some surface sites are common interfaces for crystal contacts, which means that they are surfaces that are relatively easy to desolvate and complement with organic molecules. MixMD should identify these sites; in fact, their occupancy values help establish a solid cut‐off where “druggable” sites are required to have higher occupancies than the crystal‐packing faces. © 2015 Wiley Periodicals, Inc. Biopolymers 105: 21–34, 2015. | en_US |
dc.publisher | Wiley Periodicals, Inc. | en_US |
dc.publisher | University of California | en_US |
dc.subject.other | dynamics | en_US |
dc.subject.other | binding sites | en_US |
dc.subject.other | allostery | en_US |
dc.title | Identifying binding hot spots on protein surfaces by mixed‐solvent molecular dynamics: HIV‐1 protease as a test case | en_US |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | en_US |
dc.subject.hlbsecondlevel | Chemical Engineering | en_US |
dc.subject.hlbsecondlevel | Chemistry | en_US |
dc.subject.hlbsecondlevel | Materials Science and Engineering | en_US |
dc.subject.hlbtoplevel | Engineering | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/116011/1/bip22742.pdf | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/116011/2/bip22742-sup-0001-suppinfo.pdf | |
dc.identifier.doi | 10.1002/bip.22742 | en_US |
dc.identifier.source | Biopolymers | en_US |
dc.identifier.citedreference | Sadiq, S. K.; De Fabritiis, G. Proteins 2010, 78, 2873 – 2885. | en_US |
dc.identifier.citedreference | Humphrey, W.; Dalke, A.; Schulten, K. J Mol Graph 1996, 14, 33 – 38. | en_US |
dc.identifier.citedreference | Schrödinger, LLC. PyMOL Molecular Graphics System. 1.5.0.1; Schrödinger, LLC: New York. 2014. | en_US |
dc.identifier.citedreference | Kohl, N. E.; Emini, E. A.; Schleif, W. A.; Davis, L. J.; Heimbach, J. C.; Dixon, R. A.; Scolnick, E. M.; Sigal, I. S. Proc Natl Acad Sci USA 1988, 85, 4686 – 4690. | en_US |
dc.identifier.citedreference | Krausslich, H. G. Proc Natl Acad Sci USA 1991, 88, 3213 – 3217. | en_US |
dc.identifier.citedreference | Galiano, L.; Ding, F.; Veloro, A. M.; Blackburn, M. E.; Simmerling, C.; Fanucci, G. E. J Am Chem Soc 2009, 131, 430 – 431. | en_US |
dc.identifier.citedreference | Hornak, V.; Abel, R.; Okur, A.; Strockbine, B.; Roitberg, A.; Simmerling, C. Proteins 2006, 65, 712 – 725. | en_US |
dc.identifier.citedreference | Ishima, R.; Louis, J. M. Proteins 2008, 70, 1408 – 1415. | en_US |
dc.identifier.citedreference | Grabuleda, X.; Jaime, C.; Kollman, P. A. J Comput Chem 2000, 21, 901 – 908. | en_US |
dc.identifier.citedreference | Damm, K. L.; Ung, P. M.; Quintero, J. J.; Gestwicki, J. E.; Carlson, H. A. Biopolymers 2008, 89, 643 – 652. | en_US |
dc.identifier.citedreference | Ung, P. M.; Dunbar, J. B.; Gestwicki, J. E.; Carlson, H. A. J Med Chem 2014, 57, 6468 – 6478. | en_US |
dc.identifier.citedreference | Perryman, A. L.; Zhang, Q.; Soutter, H. H.; Rosenfeld, R.; McRee, D. E.; Olson, A. J.; Elder, J. E.; Stout, C. D. Chem Biol Drug Des 2010, 75, 257 – 268. | en_US |
dc.identifier.citedreference | Tiefenbrunn, T.; Forli, S.; Baksh, M. M.; Chang, M. W.; Happer, M.; Lin, Y. C.; Perryman, A. L.; Rhee, J. K.; Torbett, B. E.; Olson, A. J.; Elder, J. H.; Finn, M. G.; Stout, C. D. ACS Chem Biol 2013, 8, 1223 – 1231. | en_US |
dc.identifier.citedreference | Raman, E. P.; Yu, W.; Lakkaraju, S. K.; MacKerell, A. D. J Chem Inf Model 2013, 53, 3384 – 3398. | en_US |
dc.identifier.citedreference | Yu, W.; Lakkaraju, S. K.; Raman, E. P.; MacKerell, A. D. J Comput Aided Mol Des 2014, 28, 491 – 507. | en_US |
dc.identifier.citedreference | Jordan, S. P.; Zugay, J.; Darke, P. L.; Kuo, L. C. J Biol Chem 1992, 267, 20028 – 20032. | en_US |
dc.identifier.citedreference | Perryman, A. L.; Lin, J. H.; McCammon, J. A. Biopolymers 2006, 82, 272 – 284. | en_US |
dc.identifier.citedreference | Mittal, S.; Cai, Y.; Nalam, M. N.; Bolon, D. N.; Schiffer, C. A. J Am Chem Soc 2012, 134, 4163 – 4168. | en_US |
dc.identifier.citedreference | Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Murcko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. A. J Am Chem Soc 1995, 117, 1181 – 1182. | en_US |
dc.identifier.citedreference | Miller, M.; Schneider, J.; Sathyanarayana, B. K.; Toth, M. V.; Marshall, G. R.; Clawson, L.; Selk, L.; Kent, S. B.; Wlodawer, A. Science 1989, 246, 1149 – 1152. | en_US |
dc.identifier.citedreference | Ala, P. J.; DeLoskey, R. J.; Huston, E. E.; Jadhav, P. K.; Lam, P. Y.; Eyermann, C. J.; Hodge, C. N.; Schadt, M. C.; Lewandowski, F. A.; Weber, P. C.; McCabe, D. D.; Duke, J. L.; Chang, C. H. J Biol Chem 1998, 273, 12325 – 12331. | en_US |
dc.identifier.citedreference | Kussie, P. H.; Gorina, S.; Marechal, V.; Elenbaas, B.; Moreau, J.; et al. Science 1996, 274, 948 – 953. | en_US |
dc.identifier.citedreference | Hu, L.; Benson, M. L.; Smith, R. D.; Lerner, M. G.; Carlson, H. A. Proteins 2005, 60, 333 – 340. | en_US |
dc.identifier.citedreference | Heaslet, H.; Kutilek, V.; Morris, G. M.; Lin, Y. C.; Elder, J. H.; Torbett, B. E.; Stout, C. D. J Mol Biol 2006, 356, 967 – 981. | en_US |
dc.identifier.citedreference | Mahalingam, B.; Louis, J. M.; Reed, C. C.; Adomat, J. M.; Krouse, J.; Wang, Y. F.; Harrison, R. W.; Weber, I. T. Eur J Biochem 1999, 263, 238 – 245. | en_US |
dc.identifier.citedreference | Thompson, J. D.; Higgins, D. G.; Gibson, T. J. Nucleic Acids Res 1994, 22, 4673 – 4680. | en_US |
dc.identifier.citedreference | Ringe, D.; Mattos, C. Med Res Rev 1999, 19, 321 – 331. | en_US |
dc.identifier.citedreference | Soga, S.; Shirai, H.; Kobori, M.; Hirayama, N. J Chem Inf Model 2007, 47, 400 – 406. | en_US |
dc.identifier.citedreference | Soga, S.; Shirai, H.; Kobori, M.; Hirayama, N. J Chem Inf Model 2007, 47, 2287 – 2292. | en_US |
dc.identifier.citedreference | Tsai, C. J.; Lin, S. L.; Wolfson, H. J.; Nussinov, R. Protein Sci 1997, 6, 53 – 64. | en_US |
dc.identifier.citedreference | Allen, K. N.; Bellamacina, C. R.; Ding, X.; Jeffery, C. J.; Mattos, C.; Petsko, G. A.; Ringe, D. J Phys Chem 1996, 100, 2605 – 2611. | en_US |
dc.identifier.citedreference | English, A. C.; Groom, C. R.; Hubbard, R. E. Protein Eng 2001, 14, 47 – 59. | en_US |
dc.identifier.citedreference | Mattos, C.; Bellamacina, C. R.; Peisach, E.; Pereira, A.; Vitkup, D.; Petsko, G. A.; Ringe, D. J Mol Biol 2006, 357, 1471 – 1482. | en_US |
dc.identifier.citedreference | Mattos, C.; Ringe, D. Nat Biotechnol 1996, 14, 595 – 599. | en_US |
dc.identifier.citedreference | Wang, Z.; Zhu, G.; Huang, Q.; Qian, M.; Shao, M.; Jia, Y.; Tang, Y. Biochim Biophys Acta 1998, 1384, 335 – 344. | en_US |
dc.identifier.citedreference | Liepinsh, E.; Otting, G. Nat Biotechnol 1997, 15, 264 – 268. | en_US |
dc.identifier.citedreference | Shuker, S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S. W. Science 1996, 274, 1531 – 1534. | en_US |
dc.identifier.citedreference | Brenke, R.; Kozakov, D.; Chuang, G. Y.; Beglov, D.; Hall, D.; Landon, M. R.; Mattos, C.; Vajda, S. Bioinformatics 2009, 25, 621 – 627. | en_US |
dc.identifier.citedreference | Dennis, S.; Kortvelyesi, T.; Vajda, S. Proc Natl Acad Sci USA 2002, 99, 4290 – 4295. | en_US |
dc.identifier.citedreference | Gohlke, H.; Hendlich, M.; Klebe, G. J Mol Biol 2000, 295, 337 – 356. | en_US |
dc.identifier.citedreference | Goodford, P. J. J Med Chem 1985, 28, 849 – 857. | en_US |
dc.identifier.citedreference | Landon, M. R.; Amaro, R. E.; Baron, R.; Ngan, C. H.; Ozonoff, D.; McCammon, J. A.; Vajda, S. Chem Biol Drug Des 2008, 71, 106 – 116. | en_US |
dc.identifier.citedreference | Miranker, A.; Karplus, M. Proteins 1991, 11, 29 – 34. | en_US |
dc.identifier.citedreference | Bakan, A.; Nevins, N.; Lakdawala, A. S.; Bahar, I. J Chem Theory Comput 2012, 8, 2435 – 2447. | en_US |
dc.identifier.citedreference | Foster, T. J.; MacKerell, A. D.; Guvench, O. J Comput Chem 2012, 33, 1880 – 1891. | en_US |
dc.identifier.citedreference | Guvench, O.; MacKerell, A. D. PLoS Comput Biol 2009, 5, e1000435. | en_US |
dc.identifier.citedreference | Raman, E. P.; Vanommeslaeghe, K.; MacKerell, A. D. J Chem Theory Comput 2012, 8, 3513 – 3525. | en_US |
dc.identifier.citedreference | Raman, E. P.; Yu, W.; Guvench, O.; MacKerell, A. D. J Chem Inf Model 2011, 51, 877 – 896. | en_US |
dc.identifier.citedreference | Seco, J.; Luque, F. J.; Barril, X. J Med Chem 2009, 52, 2363 – 2371. | en_US |
dc.identifier.citedreference | Alvarez‐Garcia, D.; Barril, X. J Med Chem 2014, 57, 8530 – 8539. | en_US |
dc.identifier.citedreference | Lakkaraju, S. K.; Yu, W.; Raman, E. P.; Hershfeld, A. V.; Fang, L.; Deshpande, D. A.; MacKerell, A. D. J Chem Inf Model 2015, 55, 700 – 708. | en_US |
dc.identifier.citedreference | Knox, C.; Law, V.; Jewison, T.; Liu, P.; Ly, S.; Frolkis, A.; Pon, A.; Banco, K.; Mak, C.; Neveu, V.; Djoumbou, Y.; Eisner, R.; Guo, A. C.; Wishart, D. S. Nucleic Acids Res 2011, 39, D1035 – D1041. | en_US |
dc.identifier.citedreference | Lexa, K. W.; Carlson, H. A. J Am Chem Soc 2011, 133, 200 – 202. | en_US |
dc.identifier.citedreference | Lexa, K. W.; Carlson, H. A. J Chem Inf Model 2013, 53, 391 – 402. | en_US |
dc.identifier.citedreference | Lexa, K. W.; Goh, G. B.; Carlson, H. A. J Chem Inf Model 2014, 54, 2190 – 2199. | en_US |
dc.identifier.citedreference | Sevier, C. S.; Kaiser, C. A. Nat Rev Mol Cell Biol 2002, 3, 836 – 847. | en_US |
dc.identifier.citedreference | Spinelli, S.; Liu, Q. Z.; Alzari, P. M.; Hirel, P. H.; Poljak, R. J. Biochimie 1991, 73, 1391 – 1396. | en_US |
dc.identifier.citedreference | Sham, H. L.; Zhao, C.; Stewart, K. D.; Betebenner, D. A.; Lin, S.; Park, C. H.; Kong, X. P.; Rosenbrook, W.; Herrin, T.; Madigan, D.; Vasavanonda, S.; Lyons, N.; Molla, A.; Saldivar, A.; Marsh, K. C.; McDonald, E.; Wideburg, N. E.; Denissen, J. F.; Robins, T.; Kempf, D. J.; Plattner, J. J.; Norbeck, D. W. J Med Chem 1996, 39, 392 – 397. | en_US |
dc.identifier.citedreference | Case, D. A.; Darden, T. A.; Cheatham, T. E.; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Walker, R. C.; Zhang, W.; Merz, K. M.; Roberts, B.; Wang, B.; Hayik, S.; Roitberg, A.; Seabra, G.; Kolossváry, I.; Wong, K. F.; Paesani, F.; Vanicek, J.; Liu, J.; Wu, X.; Brozell, S. R.; Steinbrecher, T.; Gohlke, H.; Cai, Q.; Ye, X.; Wang, J.; Hsieh, M.-J.; Cui, G.; Roe, D. R.; Mathews, D. H.; Seetin, M. G.; Sagui, C.; Babin, V.; Luchko, T.; Gusarov, S.; Kovalenko, A.; Kollman, P. A. AMBER 11; University of California: San Francisco, CA, 2010. | en_US |
dc.identifier.citedreference | Hornak, V.; Okur, A.; Rizzo, R. C.; Simmerling, C. Proc Natl Acad Sci USA 2006, 103, 915 – 920. | en_US |
dc.identifier.citedreference | Ryckaert, J. P.; Ciccotti, G.; Berendsen, H. J. C. J Comput Phys 1977, 23, 327 – 341. | en_US |
dc.identifier.citedreference | Darden, T. A.; York, D. M.; Pedersen, L. G. J Chem Phys 1993, 98, 10089 – 10092. | en_US |
dc.identifier.citedreference | Andrea, T. A.; Swope, W. C.; Andersen, H. C. J Chem Phys 1983, 79, 4576 – 4584. | en_US |
dc.identifier.citedreference | Jorgensen, W. L.; Maxwell, D. S.; Tirado‐Rives, J. J Am Chem Soc 1996, 118, 11225 – 11236. | en_US |
dc.identifier.citedreference | Jorgensen, W. L.; McDonald, N. A. J Mol Struct (Theochem) 1998, 424, 145 – 155. | en_US |
dc.identifier.citedreference | Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. J Chem Phys 1983, 79, 926 – 935. | en_US |
dc.identifier.citedreference | Goetz, A. W.; Williamson, M. J.; Xu, D.; Poole, D.; Grand, S. L.; et al. J Chem Theory Comput 2012, 8, 1542 – 1555. | en_US |
dc.identifier.citedreference | Amadei, A.; Linssen, A. B.; Berendsen, H. J. Proteins 1993, 17, 412 – 425. | en_US |
dc.identifier.citedreference | Garcia, A. E. Phys Rev Lett 1992, 68, 2696 – 2699. | en_US |
dc.identifier.citedreference | Mongan, J. J Comput Aided Mol Des 2004, 18, 433 – 436. | en_US |
dc.identifier.citedreference | Barrett, C. P.; Hall, B. A.; Noble, M. E. Acta Crystallogr D Biol Crystallogr 2004, 60, 2280 – 2287. | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.