Gaussian Accelerated Molecular Dynamics in Drug Discovery

Chapter 2 Gaussian Accelerated Molecular Dynamics in Drug Discovery Hung N. Do, Hung N. Do Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047 USASearch for more papers by this authorJinan Wang, Jinan Wang Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047 USASearch for more papers by this authorKeya Joshi, Keya Joshi Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047 USASearch for more papers by this authorKushal Koirala, Kushal Koirala Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047 USASearch for more papers by this authorYinglong Miao, Yinglong Miao Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047 USASearch for more papers by this author Hung N. Do, Hung N. Do Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047 USASearch for more papers by this authorJinan Wang, Jinan Wang Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047 USASearch for more papers by this authorKeya Joshi, Keya Joshi Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047 USASearch for more papers by this authorKushal Koirala, Kushal Koirala Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047 USASearch for more papers by this authorYinglong Miao, Yinglong Miao Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66047 USASearch for more papers by this author Book Editor(s):Vasanthanathan Poongavanam, Vasanthanathan Poongavanam Uppsala University, Uppsala, 75105 SwedenSearch for more papers by this authorVijayan Ramaswamy, Vijayan Ramaswamy Univ. Texas MD Anderson Cancer Center, Houston, 77054 United StatesSearch for more papers by this author First published: 19 January 2024 https://doi.org/10.1002/9783527840748.ch2 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onEmailFacebookTwitterLinkedInRedditWechat Summary This chapter summarizes recent methodological developments and application studies of Gaussian accelerated molecular dynamics (GaMD) in drug discovery. GaMD is an unconstrained enhanced sampling technique that allows for exploration of the conformational space of proteins and understanding of complex biological interactions that often occur on millisecond and longer timescales. The boost potential in GaMD usually exhibits a Gaussian distribution, enabling accurate reweighting of the simulations using cumulant expansion to the second order. Recently developed "selective GaMD" algorithms such as ligand GaMD (LiGaMD), peptide GaMD (Pep-GaMD), and protein–protein interaction GaMD (PPI-GaMD) have enabled microsecond-timescale all-atom simulations to characterize the binding thermodynamics and kinetics of small molecules, flexible peptides, and proteins. GaMD has been successfully applied to reveal the mechanisms of ligand/drug binding to various biomolecules (including GPCRs, nucleic acids, and human ACE2 receptors), as well as generating protein structures for virtual screening in drug discovery. References Karplus , M. and McCammon , J.A. ( 2002 ). Nat. Struct. Biol. 9 : 646 – 652 , https://doi.org/10.1038/Nsb0902-646 . 10.1038/nsb0902-646 CASPubMedWeb of Science®Google Scholar Hollingsworth , S. and Dror , R. ( 2018 ). Neuron 99 : 1129 – 1143 . 10.1016/j.neuron.2018.08.011 CASPubMedWeb of Science®Google Scholar Wang , J. et al. ( 2021 ). WIREs Comput. Mol. Sci. e1521 , https://doi.org/10.1002/wcms.1521 . 10.1002/wcms.1521 Google Scholar Henzler-Wildman , K. and Kern , D. ( 2007 ). Nature 450 : 964 – 972 . 10.1038/nature06522 CASPubMedWeb of Science®Google Scholar Harvey , M.J. , Giupponi , G. , and Fabritiis , G.D. ( 2009 ). J. Chem. Theory Comput. 5 : 1632 – 1639 . 10.1021/ct9000685 CASPubMedWeb of Science®Google Scholar Johnston , J.M. and Filizola , M. ( 2011 ). Curr. Opin. Struct. Biol. 21 : 552 – 558 . 10.1016/j.sbi.2011.06.008 CASPubMedWeb of Science®Google Scholar Shaw , D.E. et al. ( 2010 ). Science 330 : 341 – 346 . 10.1126/science.1187409 CASPubMedWeb of Science®Google Scholar Lane , T.J. , Shukla , D. , Beauchamp , K.A. , and Pande , V.S. ( 2013 ). Curr. Opin. Struct. Biol. 23 : 58 – 65 . 10.1016/j.sbi.2012.11.002 CASPubMedWeb of Science®Google Scholar Vilardaga , J.-P. , Bünemann , M. , Krasel , C. et al. ( 2008 ). Nat. Biotechnol. 21 : 807 – 812 . 10.1038/nbt838 Google Scholar Miao , Y. and Ortoleva , P.J. ( 2006 ). J. Chem. Phys. 125 : 214901 . 10.1063/1.2400858 PubMedWeb of Science®Google Scholar Spiwok , V. , Sucur , Z. , and Hosek , P. ( 2015 ). Biotechnol. Adv. 33 : 1130 – 1140 . 10.1016/j.biotechadv.2014.11.011 CASPubMedWeb of Science®Google Scholar Gao , Y.Q. , Yang , L.J. , Fan , Y.B. , and Shao , Q. ( 2008 ). Int. Rev. Phys. Chem. 27 : 201 – 227 . 10.1080/01442350801920334 CASWeb of Science®Google Scholar Liwo , A. , Czaplewski , C. , Oldziej , S. , and Scheraga , H.A. ( 2008 ). Curr. Opin. Struct. Biol. 18 : 134 – 139 . 10.1016/j.sbi.2007.12.001 CASPubMedWeb of Science®Google Scholar Christen , M. and van Gunstere , W. ( 2008 ). J. Comput. Chem. 29 : 157 – 166 . 10.1002/jcc.20725 CASPubMedWeb of Science®Google Scholar Miao , Y. and McCammon , J.A. ( 2016 ). Mol. Simul. 42 : 1046 – 1055 . 10.1080/08927022.2015.1121541 CASPubMedWeb of Science®Google Scholar Torrie , G. and Valleau , J. ( 1977 ). J. Comput. Phys. 23 : 187 – 199 . 10.1016/0021-9991(77)90121-8 Web of Science®Google Scholar Kumar , S. , Rosenberg , J. , Bouzida , D. et al. ( 1992 ). J. Comput. Chem. 13 : 1011 – 1021 . 10.1002/jcc.540130812 CASWeb of Science®Google Scholar Laio , A. and Gervasio , F. ( 2008 ). Rep. Prog. Phys. 71 : 126601 . 10.1088/0034-4885/71/12/126601 CASWeb of Science®Google Scholar Besker , N. and Gervasio , F. ( 2012 ). Computational Drug Discovery and Design , 501 – 513 . Berlin : Springer . 10.1007/978-1-61779-465-0_29 Google Scholar Darve , E. , Rodriguez-Gomez , D. , and Pohorille , A. ( 2008 ). J. Chem. Phys. 128 : 144120 . 10.1063/1.2829861 CASPubMedWeb of Science®Google Scholar Darve , E. , Wilson , M. , and Pohorille , A. ( 2002 ). Mol. Simul. 28 : 113 – 144 . 10.1080/08927020211975 CASWeb of Science®Google Scholar Isralewitz , B. , Baudry , J. , Gullingsrud , J. et al. ( 2001 ). J. Mol. Graph. Model. 19 : 13 – 25 . 10.1016/S1093-3263(00)00133-9 CASPubMedWeb of Science®Google Scholar Sugita , Y. and Okamoto , Y. ( 1999 ). Chem. Phys. Lett. 314 : 141 – 151 . 10.1016/S0009-2614(99)01123-9 CASWeb of Science®Google Scholar Okamoto , Y. ( 2004 ). J. Mol. Graph. Model. 22 : 425 – 439 . 10.1016/j.jmgm.2003.12.009 CASPubMedWeb of Science®Google Scholar Hansmann , U. ( 1997 ). Chem. Phys. Lett. 281 : 140 – 150 . 10.1016/S0009-2614(97)01198-6 CASWeb of Science®Google Scholar Wu , X. and Brooks , B. ( 2003 ). Chem. Phys. Lett. 381 : 512 – 518 . 10.1016/j.cplett.2003.10.013 CASWeb of Science®Google Scholar Wu , X. , Brooks , B. , and Vanden-Eijnden , E. ( 2016 ). J. Comput. Chem. 37 : 595 – 601 . 10.1002/jcc.24015 CASPubMedWeb of Science®Google Scholar Wu , X. and Wang , S. ( 1998 ). J. Phys. Chem. B. 102 : 7238 – 7250 . 10.1021/jp9817372 CASWeb of Science®Google Scholar Hamelberg , D. , Mongan , J. , and McCammon , J.A. ( 2004 ). J. Chem. Phys. 120 : 11919 – 11929 . 10.1063/1.1755656 CASPubMedWeb of Science®Google Scholar Voter , A. and Hyperdynamics , F. ( 1997 ). Phys. Rev. Lett. 78 : 3908 . 10.1103/PhysRevLett.78.3908 CASWeb of Science®Google Scholar Miao , Y. , Feher , V.A. , and McCammon , J.A. ( 2015 ). J. Chem. Theory Comput. 11 : 3584 – 3595 . 10.1021/acs.jctc.5b00436 CASPubMedWeb of Science®Google Scholar Miao , Y. et al. ( 2014 ). J. Chem. Theory Comput. 10 : 2677 – 2689 . 10.1021/ct500090q CASPubMedWeb of Science®Google Scholar Do , H. , Akhter , S. , and Miao , Y. ( 2021 ). Front. Mol. Biosci. 8 : 242 . 10.3389/fmolb.2021.673170 Google Scholar Bhattarai , A. , Pawnikar , S. , and Miao , Y. ( 2021 ). J. Phys. Chem. Lett. 12 : 4814 – 4822 . 10.1021/acs.jpclett.1c01064 CASPubMedWeb of Science®Google Scholar Pang , Y. , Miao , Y. , and McCammon , J.A. ( 2017 ). J. Chem. Theory Comput. 13 : 9 – 19 . 10.1021/acs.jctc.6b00931 CASPubMedWeb of Science®Google Scholar Tang , Z. et al. ( 2021 ). Nucleic Acids Res. 49 : 7870 – 7883 . 10.1093/nar/gkab602 CASPubMedWeb of Science®Google Scholar Do , H. , Wang , J. , Bhattarai , A. , and Miao , Y. ( 2022 ). J. Chem. Theory Comput. 18 : 1423 – 1436 . 10.1021/acs.jctc.1c01055 CASPubMedWeb of Science®Google Scholar Bhattarai , A. , Devkota , S. , Bhattarai , S. et al. ( 2020 ). ACS Central Sci. 6 : 969 – 983 . 10.1021/acscentsci.0c00296 CASPubMedWeb of Science®Google Scholar Bhattarai , A. et al. ( 2022 ). J. Am. Chem. Soc. 144 : 6215 – 6226 . 10.1021/jacs.1c10533 CASPubMedWeb of Science®Google Scholar Miao , Y. and McCammon , J.A. ( 2016 ). Proc. Natl. Acad. Sci. U. S. A. 113 : 12162 – 12167 . 10.1073/pnas.1614538113 CASPubMedWeb of Science®Google Scholar Bhattarai , A. , Wang , J. , and Miao , Y. ( 2020 ). J. Comput. Chem. 41 : 460 – 471 . 10.1002/jcc.26082 CASPubMedWeb of Science®Google Scholar Miao , Y. and McCammon , J.A. ( 2018 ). Proc. Natl. Acad. Sci. U. S. A. 115 : 3036 – 3041 . 10.1073/pnas.1800756115 CASPubMedWeb of Science®Google Scholar Wang , J. and Miao , Y. ( 2019 ). J. Phys. Chem. B. 123 : 6462 – 6473 . 10.1021/acs.jpcb.9b04867 CASPubMedWeb of Science®Google Scholar Wang , J. and Miao , Y. ( 2022 ). J. Chem. Theory Comput. 18 : 1275 – 1285 . 10.1021/acs.jctc.1c00974 CASPubMedWeb of Science®Google Scholar East , K.W. et al. ( 2020 ). J. Am. Chem. Soc. 142 : 1348 – 1358 . 10.1021/jacs.9b10521 CASPubMedWeb of Science®Google Scholar Ricci , C.G. et al. ( 2019 ). ACS Central Sci. 5 : 651 – 662 . 10.1021/acscentsci.9b00020 CASPubMedWeb of Science®Google Scholar Huang , Y.-M. , McCammon , J.A. , and Miao , Y. ( 2018 ). J. Chem. Theory Comput. 14 : 1853 – 1864 . 10.1021/acs.jctc.7b01226 CASPubMedWeb of Science®Google Scholar Oshima , H. , Re , S. , and Sugita , Y. ( 2019 ). J. Chem. Theory Comput. 15 : 5199 – 5208 . 10.1021/acs.jctc.9b00761 CASPubMedWeb of Science®Google Scholar Ahn , S.H. , Ojha , A.A. , Amaro , R.E. , and McCammon , J.A. ( 2021 ). J. Chem. Theory Comput. 17 : 7938 – 7951 . 10.1021/acs.jctc.1c00770 CASPubMedWeb of Science®Google Scholar Ponder , J.W. et al. ( 2010 ). J. Phys. Chem. B. 8 : 2549 – 2564 . 10.1021/jp910674d Google Scholar Shi , Y. et al. ( 2013 ). J. Chem. Theory Comput. 9 : 4046 – 4063 . 10.1021/ct4003702 CASPubMedWeb of Science®Google Scholar Zhang , C. et al. ( 2018 ). J. Chem. Theory Comput. 14 : 2084 – 2108 . 10.1021/acs.jctc.7b01169 CASPubMedWeb of Science®Google Scholar Lagardere , L. et al. ( 2018 ). Chem. Sci. 9 : 956 – 972 . 10.1039/C7SC04531J CASPubMedWeb of Science®Google Scholar Adjoua , O. et al. ( 2021 ). J. Chem. Theory Comput. 17 : 2034 – 2053 . 10.1021/acs.jctc.0c01164 CASPubMedWeb of Science®Google Scholar Miao , Y. , Bhattarai , A. , and Wang , J. ( 2020 ). J. Chem. Theory Comput. 16 : 5526 – 5547 . 10.1021/acs.jctc.0c00395 CASPubMedWeb of Science®Google Scholar Wang , J. and Miao , Y. ( 2020 ). J. Chem. Phys. 153 : 154109 . 10.1063/5.0021399 CASPubMedWeb of Science®Google Scholar Miao , Y. and McCammon , J.A. ( 2017 ). Annu. Rep. Comp. Chem. 13 : 231 – 278 , https://doi.org/10.1016/bs.arcc.2017.06.005 . 10.1016/bs.arcc.2017.06.005 PubMedGoogle Scholar Keras-Vis ( GitHub , 2017 ). Google Scholar Miao , Y. ( 2018 ). J. Chem. Phys. 149 : 072308 , https://doi.org/10.1063/1.5024217 . 10.1063/1.5024217 PubMedGoogle Scholar Doshi , U. and Hamelberg , D. ( 2011 ). J. Chem. Theory Comput. 7 : 575 – 581 , https://doi.org/10.1021/ct1005399 . 10.1021/ct1005399 CASPubMedWeb of Science®Google Scholar Frank , A.T. and Andricioaei , I. ( 2016 ). J. Phys. Chem. B 120 : 8600 – 8605 , https://doi.org/10.1021/acs.jpcb.6b02654 . 10.1021/acs.jpcb.6b02654 CASPubMedWeb of Science®Google Scholar Hamelberg , D. , Shen , T. , and Andrew McCammon , J. ( 2005 ). J. Chem. Phys. 122 : 241103 , https://doi.org/10.1063/1.1942487 . 10.1063/1.1942487 CASPubMedWeb of Science®Google Scholar Celerse , F. et al. ( 2022 ). J. Chem. Theory Comput. 18 : 968 – 977 . 10.1021/acs.jctc.1c01024 CASPubMedWeb of Science®Google Scholar Copeland , M.C. et al. ( 2022 ). J. Phys. Chem. B. 126 : 5810 – 5820 . 10.1021/acs.jpcb.2c03765 CASPubMedWeb of Science®Google Scholar Hauser , A.S. et al. ( 2018 ). Cell 172 : 41 – 54 . 10.1016/j.cell.2017.11.033 CASPubMedWeb of Science®Google Scholar Stevens , R.C. et al. ( 2013 ). Nat. Rev. Drug Discov. 12 : 25 – 34 . 10.1038/nrd3859 CASPubMedWeb of Science®Google Scholar Isberg , V. et al. ( 2016 ). Nucleic Acids Res. 44 : D365 – D364 . 10.1093/nar/gkv1178 PubMedWeb of Science®Google Scholar Fredholm , B. et al. ( 1997 ). Trends Pharmacol. Sci. 18 : 79 – 82 . 10.1016/S0165-6147(96)01038-3 CASPubMedWeb of Science®Google Scholar Jacobson , K.A. and Gao , Z.-G. ( 2006 ). Nat. Rev. Drug Discov. 5 : 247 – 264 . 10.1038/nrd1983 CASPubMedWeb of Science®Google Scholar Cheng , R. et al. ( 2017 ). Structure 25 : 1275 – 1285 . 10.1016/j.str.2017.06.012 CASPubMedWeb of Science®Google Scholar Draper-Joyce , C.J. et al. ( 2021 ). Nature 597 : 571 – 576 , https://doi.org/10.1038/s41586-021-03897-2 . 10.1038/s41586-021-03897-2 CASPubMedWeb of Science®Google Scholar Dror , R.O. et al. ( 2011 ). Proc. Natl. Acad. Sci. U. S. A. 108 : 18684 – 18689 . 10.1073/pnas.1110499108 CASPubMedWeb of Science®Google Scholar Avlani , V. et al. ( 2007 ). J. Biol. Chem. 282 : 25677 – 25686 . 10.1074/jbc.M702311200 CASPubMedWeb of Science®Google Scholar Peeters , M. et al. ( 2012 ). Biochem. Pharmacol. 84 : 76 – 87 . 10.1016/j.bcp.2012.03.008 CASPubMedWeb of Science®Google Scholar Nguyen , A. et al. ( 2016 ). Mol. Pharmacol. 90 : 715 – 725 . 10.1124/mol.116.105015 CASPubMedWeb of Science®Google Scholar Miao , Y. , Bhattarai , A. , Nguyen , A. et al. ( 2018 ). Sci. Rep. 8 : 16836 . 10.1038/s41598-018-35266-x PubMedWeb of Science®Google Scholar Wang , J. et al. ( 2020 ). GPCRs (ed. B. Jastrzebska and P.S.H. Park ), 283 – 293 . Academic Press . 10.1016/B978-0-12-816228-6.00015-5 Google Scholar Morris , G.M. et al. ( 2009 ). J. Comput. Chem. 30 : 2785 – 2791 . 10.1002/jcc.21256 CASPubMedWeb of Science®Google Scholar Bhattarai , A. , Wang , J. , and Miao , Y. ( 2020 ). Biochim. Biophys. Acta Gen. Subj. 1864 : 129615 . 10.1016/j.bbagen.2020.129615 CASPubMedWeb of Science®Google Scholar Amber 2021 ( University of California, San Francisco , 2021 ). Google Scholar Ivani , I. et al. ( 2016 ). Nat. Methods 13 : 55 – 58 . 10.1038/nmeth.3658 CASPubMedWeb of Science®Google Scholar Zgarbova , M. , Otyepka , M. , Šponer , J. et al. ( 2011 ). J. Chem. Theory Comput. 7 : 2866 – 2902 . 10.1021/ct200162x Google Scholar Wang , J. , Wolf , R. , Caldwell , J. et al. ( 2004 ). J. Comput. Chem. 25 : 1157 – 1174 . 10.1002/jcc.20035 CASPubMedWeb of Science®Google Scholar Mark , P. and Nilsson , L. ( 2001 ). Chem. A Eur. J. 105 : 9954 – 9960 . CASGoogle Scholar Wang , J. , Lan , L. , Wu , X. , Xu , L. & Miao , Y. bioRxiv, 2020.2010.2030.362756, https://doi.org/10.1101/2020.10.30.362756 ( 2021 ). 10.1101/2020.10.30.362756 Google Scholar Kudinov , A.E. , Karanicolas , J. , Golemis , E.A. , and Boumber , Y. ( 2017 ). Clin. Cancer Res. 23 : 2143 – 2153 , https://doi.org/10.1158/1078-0432.Ccr-16-2728 . 10.1158/1078-0432.CCR-16-2728 CASPubMedWeb of Science®Google Scholar Gross , L.Z.F. et al. ( 2020 ). ChemMedChem 15 : 1682 – 1690 , https://doi.org/10.1002/cmdc.202000368 . 10.1002/cmdc.202000368 CASPubMedWeb of Science®Google Scholar Hoffmann , M. et al. ( 2020 ). Cell 181 : 271 . 10.1016/j.cell.2020.02.052 CASPubMedWeb of Science®Google Scholar Towler , P. et al. ( 2004 ). J. Biol. Chem. 279 : 17996 – 18007 . 10.1074/jbc.M311191200 CASPubMedWeb of Science®Google Scholar Remme , W.J. and Swedberg , K. ( 2001 ). Eur. Heart J. 22 : 1527 – 1560 , https://doi.org/10.1053/euhj.2001.2783 . 10.1053/euhj.2001.2783 CASPubMedWeb of Science®Google Scholar Coldren , W.H. , Tikunova , S.B. , Davis , J.P. , and Lindert , S. ( 2020 ). J. Chem. Inf. Model. 60 : 3648 – 3661 , https://doi.org/10.1021/acs.jcim.0c00452 . 10.1021/acs.jcim.0c00452 CASPubMedWeb of Science®Google Scholar Schuetz , D.A. et al. ( 2017 ). Drug Discov. Today 22 : 896 – 911 , https://doi.org/10.1016/j.drudis.2017.02.002 . 10.1016/j.drudis.2017.02.002 CASPubMedWeb of Science®Google Scholar Tonge , P. and Drug-Target , J. ( 2018 ). ACS Chem. Nerosci. 9 : 29 – 39 , https://doi.org/10.1021/acschemneuro.7b00185 . 10.1021/acschemneuro.7b00185 CASPubMedWeb of Science®Google Scholar Ahmad , M. and Helms , V. ( 2009 ). Chem. Cent. J. 3 : O22 . 10.1186/1752-153X-3-S1-O22 Google Scholar Ball , L.J. , Kuhne , R. , Schneider-Mergener , J. , and Oschkinat , H. ( 2005 ). Angew. Chem. Int. Ed. Engl. 44 : 2852 – 2869 , https://doi.org/10.1002/anie.200400618 . 10.1002/anie.200400618 CASPubMedWeb of Science®Google Scholar Schreiber , G. and Fersht , A.R. ( 1993 ). Biochemistry 32 : 5145 – 5150 . 10.1021/bi00070a025 CASPubMedWeb of Science®Google Scholar Sztain , T. , Amaro , R.E. , and McCammon , J.A. ( 2021 ). J. Chem. Inf. Model. 61 : 3495 – 3501 . 10.1021/acs.jcim.1c00140 CASPubMedWeb of Science®Google Scholar Wang , Y.-T. et al. ( 2022 ). Phys. Chem. Chem. Phys. 24 : 22898 – 22904 . 10.1039/D2CP02882D CASPubMedWeb of Science®Google Scholar Zhang , H. et al. ( 2021 ). Nat. Commun. 12 : 4151 . 10.1038/s41467-021-24438-5 CASPubMedWeb of Science®Google Scholar Computational Drug Discovery: Methods and Applications ReferencesRelatedInformation