{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:17:11Z","timestamp":1791836231506,"version":"4.3.4"},"reference-count":91,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Science, Innovation and Universities","award":["PGC2018-099277-B-C21"],"award-info":[{"award-number":["PGC2018-099277-B-C21"]}]},{"name":"Spanish Ministry of Science, Innovation and Universities","award":["PID2021-124297NB-C32"],"award-info":[{"award-number":["PID2021-124297NB-C32"]}]},{"name":"Spanish Ministry of Science, Innovation and Universities","award":["MCIN\/ AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/ AEI\/10.13039\/501100011033"]}]},{"name":"Spanish Ministry of Science, Innovation and Universities","award":["202006230070"],"award-info":[{"award-number":["202006230070"]}]},{"name":"Spanish Ministry of Science, Innovation and Universities","award":["FI-2022-2-0004"],"award-info":[{"award-number":["FI-2022-2-0004"]}]},{"name":"FEDER Una manera de hacer Europa","award":["PGC2018-099277-B-C21"],"award-info":[{"award-number":["PGC2018-099277-B-C21"]}]},{"name":"FEDER Una manera de hacer Europa","award":["PID2021-124297NB-C32"],"award-info":[{"award-number":["PID2021-124297NB-C32"]}]},{"name":"FEDER Una manera de hacer Europa","award":["MCIN\/ AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/ AEI\/10.13039\/501100011033"]}]},{"name":"FEDER Una manera de hacer Europa","award":["202006230070"],"award-info":[{"award-number":["202006230070"]}]},{"name":"FEDER Una manera de hacer Europa","award":["FI-2022-2-0004"],"award-info":[{"award-number":["FI-2022-2-0004"]}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["PGC2018-099277-B-C21"],"award-info":[{"award-number":["PGC2018-099277-B-C21"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["PID2021-124297NB-C32"],"award-info":[{"award-number":["PID2021-124297NB-C32"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["MCIN\/ AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/ AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["202006230070"],"award-info":[{"award-number":["202006230070"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["FI-2022-2-0004"],"award-info":[{"award-number":["FI-2022-2-0004"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006433","name":"Barcelona Supercomputing Center-Spanish Supercomputing Network","doi-asserted-by":"publisher","award":["PGC2018-099277-B-C21"],"award-info":[{"award-number":["PGC2018-099277-B-C21"]}],"id":[{"id":"10.13039\/501100006433","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006433","name":"Barcelona Supercomputing Center-Spanish Supercomputing Network","doi-asserted-by":"publisher","award":["PID2021-124297NB-C32"],"award-info":[{"award-number":["PID2021-124297NB-C32"]}],"id":[{"id":"10.13039\/501100006433","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006433","name":"Barcelona Supercomputing Center-Spanish Supercomputing Network","doi-asserted-by":"publisher","award":["MCIN\/ AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/ AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/501100006433","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006433","name":"Barcelona Supercomputing Center-Spanish Supercomputing Network","doi-asserted-by":"publisher","award":["202006230070"],"award-info":[{"award-number":["202006230070"]}],"id":[{"id":"10.13039\/501100006433","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006433","name":"Barcelona Supercomputing Center-Spanish Supercomputing Network","doi-asserted-by":"publisher","award":["FI-2022-2-0004"],"award-info":[{"award-number":["FI-2022-2-0004"]}],"id":[{"id":"10.13039\/501100006433","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>KRAS-G12D mutations are the one of most frequent oncogenic drivers in human cancers. Unfortunately, no therapeutic agent directly targeting KRAS-G12D has been clinically approved yet, with such mutated species remaining undrugged. Notably, cofactor Mg2+ is closely related to the function of small GTPases, but no investigation has been conducted yet on Mg2+ when associated with KRAS. Herein, through microsecond scale molecular dynamics simulations, we found that Mg2+ plays a crucial role in the conformational changes of the KRAS-GDP complex. We located two brand new druggable dynamic pockets exclusive to KRAS-G12D. Using the structural characteristics of these two dynamic pockets, we designed in silico the inhibitor DBD15-21-22, which can specifically and tightly target the KRAS-G12D-GDP-Mg2+ ternary complex. Overall, we provide two brand new druggable pockets located on KRAS-G12D and suitable strategies for its inhibition.<\/jats:p>","DOI":"10.3390\/ijms232213865","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T19:16:23Z","timestamp":1668107783000},"page":"13865","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Discovering and Targeting Dynamic Drugging Pockets of Oncogenic Proteins: The Role of Magnesium in Conformational Changes of the G12D Mutated Kirsten Rat Sarcoma-Guanosine Diphosphate Complex"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2439-6241","authenticated-orcid":false,"given":"Zheyao","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B5-209 Northern Campus UPC, 08034 Barcelona, Catalonia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3721-9634","authenticated-orcid":false,"given":"Jordi","family":"Marti","sequence":"additional","affiliation":[{"name":"Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B5-209 Northern Campus UPC, 08034 Barcelona, Catalonia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1152\/physrev.00003.2012","article-title":"Regulation of small gtpases by gefs, gaps, and gdis","volume":"93","author":"Cherfils","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrd.2016.139","article-title":"Direct small-molecule inhibitors of KRAS: From structural insights to mechanism-based design","volume":"15","author":"Ostrem","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1126\/science.1062023","article-title":"The guanine nucleotide-binding switch in three dimensions","volume":"294","author":"Vetter","year":"2001","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nrclinonc.2009.111","article-title":"Implications for KRAS status and EGFR-targeted therapies in metastatic CRC","volume":"6","author":"Normanno","year":"2009","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ccr.2012.07.024","article-title":"EGF receptor is required for KRAS-induced pancreatic tumorigenesis","volume":"22","author":"Ardito","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.ccr.2012.08.001","article-title":"EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma","volume":"22","author":"Navas","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/0092-8674(92)90076-O","article-title":"ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK","volume":"68","author":"Wood","year":"1992","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0092-8674(92)90361-F","article-title":"Activation of the MAP kinase pathway by the protein kinase raf","volume":"71","author":"Howe","year":"1992","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7908","DOI":"10.1073\/pnas.88.18.7908","article-title":"Association of p21ras with phosphatidylinositol 3-kinase","volume":"88","author":"Yamamoto","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/370527a0","article-title":"Phosphatidylinositol-3-OH kinase direct target of Ras","volume":"370","author":"Warne","year":"1994","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11089","DOI":"10.1073\/pnas.91.23.11089","article-title":"Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator","volume":"91","author":"Hofer","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12609","DOI":"10.1073\/pnas.91.26.12609","article-title":"Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap","volume":"91","author":"Spaargaren","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12138","DOI":"10.1073\/pnas.192453199","article-title":"The structural basis for the transition from Ras-GTP to Ras-GDP","volume":"99","author":"Hall","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15858","DOI":"10.1002\/ange.201608653","article-title":"Microsecond timescale dynamics of GDP-bound Ras underlies the formation of novel inhibitor-binding pockets","volume":"128","author":"Mao","year":"2016","journal-title":"Angew. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1042\/BST20170569","article-title":"Allostery and dynamics in small G proteins","volume":"46","author":"Mott","year":"2018","journal-title":"Biochem. Soc. Trans."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1007\/s10555-020-09917-3","article-title":"Dynamically encoded reactivity of Ras enzymes: Opening new frontiers for drug discovery","volume":"39","author":"Perczel","year":"2020","journal-title":"Cancer Metastasis Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"104639","DOI":"10.1016\/j.compbiomed.2021.104639","article-title":"Conformational transformation of switch domains in GDP\/K-Ras induced by G13 mutants: An investigation through Gaussian accelerated molecular dynamics simulations and principal component analysis","volume":"135","author":"Chen","year":"2021","journal-title":"Comput. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1021\/acs.jcim.0c01470","article-title":"Mutation-induced impacts on the switch transformations of the GDP-and GTP-bound K-ras: Insights from multiple replica Gaussian accelerated molecular dynamics and free energy analysis","volume":"61","author":"Chen","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nature12796","article-title":"K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions","volume":"503","author":"Ostrem","year":"2013","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1158\/2159-8290.CD-15-1105","article-title":"Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state","volume":"6","author":"Patricelli","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1126\/science.aad6204","article-title":"Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism","volume":"351","author":"Lito","year":"2016","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.cell.2018.01.006","article-title":"Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor","volume":"172","author":"Janes","year":"2018","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1021\/acs.jmedchem.9b01180","article-title":"Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors","volume":"63","author":"Lanman","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41586-019-1694-1","article-title":"The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity","volume":"575","author":"Canon","year":"2019","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1158\/2159-8290.CD-19-1167","article-title":"The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and PatientsTherapeutic Insight from the KRASG12C Inhibitor MRTX849","volume":"10","author":"Hallin","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/s41587-021-01053-9","article-title":"Oncologists greet Lumakras: The world\u2019s first KRAS inhibitor","volume":"39","author":"Sheridan","year":"2021","journal-title":"Nat. Biotechnol."},{"key":"ref_27","first-page":"12","article-title":"Sotorasib (Lumakras\u2122)","volume":"43","author":"Mann","year":"2021","journal-title":"Oncol. Times"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15823","DOI":"10.1073\/pnas.1904529116","article-title":"Drugging an undruggable pocket on KRAS","volume":"116","author":"Kessler","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.4155\/fmc-2020-0221","article-title":"Drugging all RAS isoforms with one pocket","volume":"12","author":"Kessler","year":"2020","journal-title":"Future Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41421-021-00368-w","article-title":"KRAS (G12D) can be targeted by potent inhibitors via formation of salt bridge","volume":"8","author":"Mao","year":"2022","journal-title":"Cell Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.1021\/acs.biochem.8b01300","article-title":"K-RasG12D has a potential allosteric small molecule binding site","volume":"58","author":"Feng","year":"2019","journal-title":"Biochemistry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.cell.2017.02.006","article-title":"Multivalent small-molecule pan-RAS inhibitors","volume":"168","author":"Welsch","year":"2017","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1021\/acscentsci.0c00514","article-title":"GTP-state-selective cyclic peptide ligands of K-Ras (G12D) block its interaction with Raf","volume":"6","author":"Zhang","year":"2020","journal-title":"ACS Cent. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1021\/acs.jmedchem.1c01688","article-title":"Identification of MRTX1133, a noncovalent, potent, and selective KRASG12D inhibitor","volume":"65","author":"Wang","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1038\/s41589-022-01065-9","article-title":"Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras (G12S)","volume":"18","author":"Zhang","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/s41589-022-00985-w","article-title":"KRAS is vulnerable to reversible switch-II pocket engagement in cells","volume":"18","author":"Vasta","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15916","DOI":"10.1021\/jacs.2c05377","article-title":"Chemoselective covalent modification of K-Ras (G12R) with a small molecule electrophile","volume":"144","author":"Zhang","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.1021\/acs.jmedchem.2c00099","article-title":"Drugging the next undruggable KRAS allele-Gly12Asp","volume":"65","author":"Zheng","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"167695","DOI":"10.1016\/j.jmb.2022.167695","article-title":"Conformational Dynamics Allows Sampling of an \u201cActive-like\u201d State by Oncogenic K-Ras-GDP","volume":"434","author":"Grudzien","year":"2022","journal-title":"J. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"D945","DOI":"10.1093\/nar\/gkq929","article-title":"COSMIC: Mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer","volume":"39","author":"Forbes","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1158\/0008-5472.CAN-11-2612","article-title":"A comprehensive survey of Ras mutations in cancer","volume":"72","author":"Prior","year":"2012","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/s41573-020-0068-6","article-title":"RAS-targeted therapies: Is the undruggable drugged?","volume":"19","author":"Moore","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e2024725118","DOI":"10.1073\/pnas.2024725118","article-title":"Unveiling the \u201cinvisible\u201d druggable conformations of GDP-bound inactive Ras","volume":"118","author":"Liu","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"21949","DOI":"10.1038\/srep21949","article-title":"The structural basis of oncogenic mutations G12, G13 and Q61 in small GTPase K-Ras4B","volume":"6","author":"Lu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1002\/prot.24786","article-title":"Binding hotspots on K-ras: Consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis","volume":"83","author":"Prakash","year":"2015","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Chen, C.C., Er, T.K., Liu, Y.Y., Hwang, J.K., Barrio, M.J., Rodrigo, M., Garcia-Toro, E., and Herreros-Villanueva, M. (2013). Computational analysis of KRAS mutations: Implications for different effects on the KRAS p. G12D and p. G13D mutations. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055793"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"9938","DOI":"10.1021\/acs.jpclett.0c02809","article-title":"Long-lasting Salt Bridges Provide the Anchoring Mechanism of Oncogenic Kirsten Rat Sarcoma Proteins at Cell Membranes","volume":"11","author":"Lu","year":"2020","journal-title":"J. Phys. Chem. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1039\/D1NR07622A","article-title":"Predicting the conformational variability of oncogenic GTP-bound G12D mutated KRas-4B proteins at zwitterionic model cell membranes","volume":"14","author":"Lu","year":"2022","journal-title":"Nanoscale"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5904","DOI":"10.1038\/onc.2008.271","article-title":"The tumor microenvironment and its role in promoting tumor growth","volume":"27","author":"Whiteside","year":"2008","journal-title":"Oncogene"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cell.2010.03.015","article-title":"Matrix metalloproteinases: Regulators of the tumor microenvironment","volume":"141","author":"Kessenbrock","year":"2010","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/S0021-9258(18)54022-9","article-title":"Kinetic and structural analysis of the Mg (2+)-binding site of the guanine nucleotide-binding protein p21H-ras","volume":"268","author":"John","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1021\/ic00081a007","article-title":"Coordination of water to magnesium cations","volume":"33","author":"Bock","year":"1994","journal-title":"Inorg. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e202201449","DOI":"10.1002\/chem.202201449","article-title":"The Importance of Mg2+-free State in Nucleotide Exchange of Oncogenic K-Ras Mutants","volume":"28","author":"Vida","year":"2022","journal-title":"Chem. A Eur. J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1002\/j.1460-2075.1986.tb04366.x","article-title":"Expression of p21 proteins in Escherichia coli and stereochemistry of the nucleotide-binding site","volume":"5","author":"Tucker","year":"1986","journal-title":"EMBO J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"10963","DOI":"10.1016\/S0021-9258(18)67333-8","article-title":"The effect of Mg2+ on the guanine nucleotide exchange rate of p21N-ras","volume":"261","author":"Hall","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"8455","DOI":"10.1016\/S0021-9258(18)47433-9","article-title":"Preparation and characterization of nucleotide-free and metal ion-free p21 \u201capoprotein\u201d","volume":"262","author":"Feuerstein","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1021\/ja01565a079","article-title":"Benzothiadiazine dioxides as novel diuretics","volume":"79","author":"Novello","year":"1957","journal-title":"J. Am. Chem. Soc."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"154303","DOI":"10.1063\/5.0065163","article-title":"Structure of benzothiadiazine at zwitterionic phospholipid cell membranes","volume":"155","author":"Hu","year":"2021","journal-title":"J. Chem. Phys."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1158\/0008-5472.CAN-17-2727","article-title":"Oncogenic Ras isoforms signaling specificity at the membrane","volume":"78","author":"Nussinov","year":"2018","journal-title":"Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"11730","DOI":"10.1038\/s41598-019-48029-z","article-title":"Oncogenic G12D mutation alters local conformations and dynamics of K-Ras","volume":"9","author":"Vatansever","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S1574-1400(06)02013-5","article-title":"Principal components analysis: A review of its application on molecular dynamics data","volume":"2","author":"Stein","year":"2006","journal-title":"Annu. Rep. Comput. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"20150202","DOI":"10.1098\/rsta.2015.0202","article-title":"Principal component analysis: A review and recent developments","volume":"374","author":"Jolliffe","year":"2016","journal-title":"Philos. Trans. R. Soc. A Math. Phys. Eng. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1103\/PhysRevE.61.449","article-title":"Dynamic properties of hydrogen-bonded networks in supercritical water","volume":"61","author":"Marti","year":"2000","journal-title":"Phys. Rev. E"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1634\/theoncologist.2015-0084","article-title":"Targeting the KRAS pathway in non-small cell lung cancer","volume":"21","author":"Tomasini","year":"2016","journal-title":"Oncologist"},{"key":"ref_65","first-page":"1","article-title":"More to the RAS Story: KRASG12C Inhibition, Resistance Mechanisms, and Moving Beyond KRASG12C","volume":"42","author":"Lietman","year":"2022","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"213622","DOI":"10.1016\/j.ccr.2020.213622","article-title":"Designing magnesium-selective ligands using coordination chemistry principles","volume":"428","author":"Walter","year":"2021","journal-title":"Coord. Chem. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Hu, Z., and Marti, J. (2022). In silico drug design of benzothiadiazine derivatives interacting with phospholipid cell membranes. Membranes, 12.","DOI":"10.1101\/2022.02.14.480348"},{"key":"ref_68","unstructured":"Frenkel, D., and Smit, B. (2001). Understanding Molecular Simulation: From Algorithms to Applications, Elsevier."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"12524","DOI":"10.1021\/jp073193m","article-title":"Liquid water confined in carbon nanochannels at high temperatures","volume":"111","author":"Nagy","year":"2007","journal-title":"J. Phys. Chem. B"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"6184","DOI":"10.1021\/acs.chemrev.8b00460","article-title":"Computational modeling of realistic cell membranes","volume":"119","author":"Marrink","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1088\/0953-8984\/6\/12\/002","article-title":"Molecular dynamics simulation of liquid water at 523 K","volume":"6","author":"Padro","year":"1994","journal-title":"J. Phys. Condens. Matter"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1063\/1.1634252","article-title":"Response to \u201cComment on \u2018An interpretation of the low-frequency spectrum of liquid water\u2019\u201d[J. Chem. Phys. 118, 452 (2003)]","volume":"120","author":"Padro","year":"2004","journal-title":"J. Chem. Phys."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1021\/jp510013q","article-title":"1H nuclear spin relaxation of liquid water from molecular dynamics simulations","volume":"119","author":"Calero","year":"2015","journal-title":"J. Phys. Chem. B"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1080\/08927029908022111","article-title":"Rotation-vibration coupling in liquid water investigated by molecular dynamics simulation","volume":"23","year":"1999","journal-title":"Mol. Simul."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1080\/08927029308022517","article-title":"Computer simulation of molecular motions in liquids: Infrared spectra of water and heavy water","volume":"11","author":"Marti","year":"1993","journal-title":"Mol. Simul."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of Simple Potential Functions for Simulating Liquid Water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/jcc.21287","article-title":"CHARMM: The biomolecular simulation program","volume":"30","author":"Brooks","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1021\/acs.jctc.5b00935","article-title":"CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM\/OpenMM simulations using the CHARMM36 additive force field","volume":"12","author":"Lee","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1002\/jcc.23354","article-title":"CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data","volume":"34","author":"Huang","year":"2013","journal-title":"J. Comput. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"D302","DOI":"10.1093\/nar\/gkj120","article-title":"The RCSB PDB information portal for structural genomics","volume":"34","author":"Kouranov","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0010-4655(95)00042-E","article-title":"GROMACS: A message-passing parallel molecular dynamics implementation","volume":"91","author":"Berendsen","year":"1995","journal-title":"Comput. Phys. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1063\/1.481893","article-title":"The aqueous solvation of sodium chloride: A Monte Carlo transition path sampling study","volume":"113","author":"Marti","year":"2000","journal-title":"J. Chem. Phys."},{"key":"ref_84","first-page":"1","article-title":"Transition path sampling","volume":"123","author":"Dellago","year":"2002","journal-title":"Adv. Chem. Phys."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"061918","DOI":"10.1103\/PhysRevE.69.061918","article-title":"Transition path sampling study of flip-flop transitions in model lipid bilayer membranes","volume":"69","author":"Marti","year":"2004","journal-title":"Phys. Rev. E"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1002\/wcms.31","article-title":"Metadynamics","volume":"1","author":"Barducci","year":"2011","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s42254-020-0153-0","article-title":"Using metadynamics to explore complex free-energy landscapes","volume":"2","author":"Bussi","year":"2020","journal-title":"Nat. Rev. Phys."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1021\/ci300363c","article-title":"Automation of the CHARMM General Force Field (CGenFF) I: Bond perception and atom typing","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.1021\/ci3003649","article-title":"Automation of the CHARMM General Force Field (CGenFF) II: Assignment of bonded parameters and partial atomic charges","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13865\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:14:01Z","timestamp":1760145241000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13865"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,10]]},"references-count":91,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232213865"],"URL":"https:\/\/doi.org\/10.3390\/ijms232213865","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,10]]}}}