{"id":"https://openalex.org/W7161172453","doi":"https://doi.org/10.1021/acs.jcim.6c00156","title":"Mutation-Driven Remodeling of the LRRK2 Kinase Free-Energy Landscape and Its Consequences for Conformational Transitions and Inhibitor Binding Affinity","display_name":"Mutation-Driven Remodeling of the LRRK2 Kinase Free-Energy Landscape and Its Consequences for Conformational Transitions and Inhibitor Binding Affinity","publication_year":2026,"publication_date":"2026-05-14","ids":{"openalex":"https://openalex.org/W7161172453","doi":"https://doi.org/10.1021/acs.jcim.6c00156","pmid":"https://pubmed.ncbi.nlm.nih.gov/42130234"},"language":"en","primary_location":{"id":"doi:10.1021/acs.jcim.6c00156","is_oa":false,"landing_page_url":"https://doi.org/10.1021/acs.jcim.6c00156","pdf_url":null,"source":{"id":"https://openalex.org/S167262187","display_name":"Journal of Chemical Information and Modeling","issn_l":"1549-9596","issn":["1549-9596","1549-960X"],"is_oa":false,"is_in_doaj":false,"is_core":true,"host_organization":"https://openalex.org/P4310320006","host_organization_name":"American Chemical Society","host_organization_lineage":["https://openalex.org/P4310320006"],"host_organization_lineage_names":["American Chemical Society"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Chemical Information and Modeling","raw_type":"journal-article"},"type":"article","indexed_in":["crossref","pubmed"],"open_access":{"is_oa":false,"oa_status":"closed","oa_url":null,"any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5122994858","display_name":"Rajesh Ghosh","orcid":null},"institutions":[{"id":"https://openalex.org/I189109744","display_name":"Indian Institute of Technology Dhanbad","ror":"https://ror.org/013v3cc28","country_code":"IN","type":"education","lineage":["https://openalex.org/I189109744"]},{"id":"https://openalex.org/I4210132178","display_name":"NOAA Chemical Sciences Laboratory","ror":"https://ror.org/03f4jbs89","country_code":"US","type":"government","lineage":["https://openalex.org/I1308126019","https://openalex.org/I1343035065","https://openalex.org/I2802992173","https://openalex.org/I4210132178","https://openalex.org/I80605987"]}],"countries":["IN","US"],"is_corresponding":false,"raw_author_name":"Rajesh Ghosh","raw_affiliation_strings":["Department of chemistry & Chemical Biology","Indian Institute of Technology (ISM) Dhanbad"],"raw_orcid":"https://orcid.org/0009-0002-9030-4966","affiliations":[{"raw_affiliation_string":"Department of chemistry & Chemical Biology","institution_ids":["https://openalex.org/I4210132178"]},{"raw_affiliation_string":"Indian Institute of Technology (ISM) Dhanbad","institution_ids":["https://openalex.org/I189109744"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5136180675","display_name":"Kousik K. Bhanja","orcid":"https://orcid.org/0009-0009-0765-3315"},"institutions":[{"id":"https://openalex.org/I189109744","display_name":"Indian Institute of Technology Dhanbad","ror":"https://ror.org/013v3cc28","country_code":"IN","type":"education","lineage":["https://openalex.org/I189109744"]},{"id":"https://openalex.org/I4210132178","display_name":"NOAA Chemical Sciences Laboratory","ror":"https://ror.org/03f4jbs89","country_code":"US","type":"government","lineage":["https://openalex.org/I1308126019","https://openalex.org/I1343035065","https://openalex.org/I2802992173","https://openalex.org/I4210132178","https://openalex.org/I80605987"]}],"countries":["IN","US"],"is_corresponding":false,"raw_author_name":"Kousik K. Bhanja","raw_affiliation_strings":["Department of chemistry & Chemical Biology","Indian Institute of Technology (ISM) Dhanbad"],"raw_orcid":"https://orcid.org/0009-0009-0765-3315","affiliations":[{"raw_affiliation_string":"Department of chemistry & Chemical Biology","institution_ids":["https://openalex.org/I4210132178"]},{"raw_affiliation_string":"Indian Institute of Technology (ISM) Dhanbad","institution_ids":["https://openalex.org/I189109744"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5084230820","display_name":"Niladri Patra","orcid":"https://orcid.org/0000-0002-0331-2670"},"institutions":[{"id":"https://openalex.org/I189109744","display_name":"Indian Institute of Technology Dhanbad","ror":"https://ror.org/013v3cc28","country_code":"IN","type":"education","lineage":["https://openalex.org/I189109744"]},{"id":"https://openalex.org/I4210132178","display_name":"NOAA Chemical Sciences Laboratory","ror":"https://ror.org/03f4jbs89","country_code":"US","type":"government","lineage":["https://openalex.org/I1308126019","https://openalex.org/I1343035065","https://openalex.org/I2802992173","https://openalex.org/I4210132178","https://openalex.org/I80605987"]}],"countries":["IN","US"],"is_corresponding":true,"raw_author_name":"Niladri Patra","raw_affiliation_strings":["Department of chemistry & Chemical Biology","Indian Institute of Technology (ISM) Dhanbad"],"raw_orcid":"https://orcid.org/0000-0002-0331-2670","affiliations":[{"raw_affiliation_string":"Department of chemistry & Chemical Biology","institution_ids":["https://openalex.org/I4210132178"]},{"raw_affiliation_string":"Indian Institute of Technology (ISM) Dhanbad","institution_ids":["https://openalex.org/I189109744"]}]}],"institutions":[],"countries_distinct_count":2,"institutions_distinct_count":2,"corresponding_author_ids":["https://openalex.org/A5084230820"],"corresponding_institution_ids":["https://openalex.org/I189109744","https://openalex.org/I4210132178"],"apc_list":null,"apc_paid":null,"fwci":0.0,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":{"value":0.58645074,"is_in_top_1_percent":false,"is_in_top_10_percent":false},"cited_by_percentile_year":null,"biblio":{"volume":"66","issue":"10","first_page":"5897","last_page":"5910"},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10085","display_name":"Parkinson's Disease Mechanisms and Treatments","score":0.8776000142097473,"subfield":{"id":"https://openalex.org/subfields/2728","display_name":"Neurology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},"topics":[{"id":"https://openalex.org/T10085","display_name":"Parkinson's Disease Mechanisms and Treatments","score":0.8776000142097473,"subfield":{"id":"https://openalex.org/subfields/2728","display_name":"Neurology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10044","display_name":"Protein Structure and Dynamics","score":0.03700000047683716,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11533","display_name":"Melanoma and MAPK Pathways","score":0.015300000086426735,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/metadynamics","display_name":"Metadynamics","score":0.7454000115394592},{"id":"https://openalex.org/keywords/active-site","display_name":"Active site","score":0.6407999992370605},{"id":"https://openalex.org/keywords/salt-bridge","display_name":"Salt bridge","score":0.6407999992370605},{"id":"https://openalex.org/keywords/molecular-dynamics","display_name":"Molecular dynamics","score":0.553600013256073},{"id":"https://openalex.org/keywords/conformational-change","display_name":"Conformational change","score":0.5496000051498413},{"id":"https://openalex.org/keywords/transition","display_name":"Transition (genetics)","score":0.5371999740600586},{"id":"https://openalex.org/keywords/mutant","display_name":"Mutant","score":0.534500002861023},{"id":"https://openalex.org/keywords/energy-landscape","display_name":"Energy landscape","score":0.4812000095844269},{"id":"https://openalex.org/keywords/allosteric-regulation","display_name":"Allosteric regulation","score":0.45750001072883606}],"concepts":[{"id":"https://openalex.org/C62752575","wikidata":"https://www.wikidata.org/wiki/Q6822487","display_name":"Metadynamics","level":3,"score":0.7454000115394592},{"id":"https://openalex.org/C30765947","wikidata":"https://www.wikidata.org/wiki/Q899119","display_name":"Salt bridge","level":4,"score":0.6407999992370605},{"id":"https://openalex.org/C41183919","wikidata":"https://www.wikidata.org/wiki/Q423026","display_name":"Active site","level":3,"score":0.6407999992370605},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.600600004196167},{"id":"https://openalex.org/C59593255","wikidata":"https://www.wikidata.org/wiki/Q901663","display_name":"Molecular dynamics","level":2,"score":0.553600013256073},{"id":"https://openalex.org/C2777339483","wikidata":"https://www.wikidata.org/wiki/Q647203","display_name":"Conformational change","level":2,"score":0.5496000051498413},{"id":"https://openalex.org/C194232998","wikidata":"https://www.wikidata.org/wiki/Q1606712","display_name":"Transition (genetics)","level":3,"score":0.5371999740600586},{"id":"https://openalex.org/C143065580","wikidata":"https://www.wikidata.org/wiki/Q3285695","display_name":"Mutant","level":3,"score":0.534500002861023},{"id":"https://openalex.org/C12554922","wikidata":"https://www.wikidata.org/wiki/Q7100","display_name":"Biophysics","level":1,"score":0.5067999958992004},{"id":"https://openalex.org/C119621388","wikidata":"https://www.wikidata.org/wiki/Q5377166","display_name":"Energy landscape","level":2,"score":0.4812000095844269},{"id":"https://openalex.org/C166342909","wikidata":"https://www.wikidata.org/wiki/Q845326","display_name":"Allosteric regulation","level":3,"score":0.45750001072883606},{"id":"https://openalex.org/C71240020","wikidata":"https://www.wikidata.org/wiki/Q186011","display_name":"Stereochemistry","level":1,"score":0.43779999017715454},{"id":"https://openalex.org/C501734568","wikidata":"https://www.wikidata.org/wiki/Q42918","display_name":"Mutation","level":3,"score":0.4359999895095825},{"id":"https://openalex.org/C184235292","wikidata":"https://www.wikidata.org/wiki/Q421851","display_name":"Kinase","level":2,"score":0.4278999865055084},{"id":"https://openalex.org/C107824862","wikidata":"https://www.wikidata.org/wiki/Q616005","display_name":"Binding site","level":2,"score":0.4077000021934509},{"id":"https://openalex.org/C47701112","wikidata":"https://www.wikidata.org/wiki/Q735188","display_name":"Protein structure","level":2,"score":0.3995000123977661},{"id":"https://openalex.org/C150109051","wikidata":"https://www.wikidata.org/wiki/Q3630494","display_name":"Autophosphorylation","level":4,"score":0.3919999897480011},{"id":"https://openalex.org/C55493867","wikidata":"https://www.wikidata.org/wiki/Q7094","display_name":"Biochemistry","level":1,"score":0.37709999084472656},{"id":"https://openalex.org/C125209161","wikidata":"https://www.wikidata.org/wiki/Q422816","display_name":"Enzyme activator","level":3,"score":0.35929998755455017},{"id":"https://openalex.org/C51639874","wikidata":"https://www.wikidata.org/wiki/Q167149","display_name":"Plasma protein binding","level":2,"score":0.3529999852180481},{"id":"https://openalex.org/C2776376580","wikidata":"https://www.wikidata.org/wiki/Q407355","display_name":"Transferase","level":3,"score":0.3384999930858612},{"id":"https://openalex.org/C2780427247","wikidata":"https://www.wikidata.org/wiki/Q409961","display_name":"LRRK2","level":4,"score":0.31859999895095825},{"id":"https://openalex.org/C89031862","wikidata":"https://www.wikidata.org/wiki/Q906964","display_name":"Transition state","level":3,"score":0.3077000081539154},{"id":"https://openalex.org/C116569031","wikidata":"https://www.wikidata.org/wiki/Q899107","display_name":"Ligand (biochemistry)","level":3,"score":0.29820001125335693},{"id":"https://openalex.org/C2777936996","wikidata":"https://www.wikidata.org/wiki/Q17148461","display_name":"Conformational ensembles","level":3,"score":0.29589998722076416},{"id":"https://openalex.org/C2776568683","wikidata":"https://www.wikidata.org/wiki/Q23005640","display_name":"Moiety","level":2,"score":0.28380000591278076},{"id":"https://openalex.org/C181199279","wikidata":"https://www.wikidata.org/wiki/Q8047","display_name":"Enzyme","level":2,"score":0.28369998931884766},{"id":"https://openalex.org/C2775981520","wikidata":"https://www.wikidata.org/wiki/Q17156992","display_name":"Protein dynamics","level":3,"score":0.2777000069618225},{"id":"https://openalex.org/C89464430","wikidata":"https://www.wikidata.org/wiki/Q849516","display_name":"Metastability","level":2,"score":0.272599995136261}],"mesh":[{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000037","qualifier_name":"antagonists & inhibitors","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000037","qualifier_name":"antagonists & inhibitors","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000037","qualifier_name":"antagonists & inhibitors","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000235","qualifier_name":"genetics","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000235","qualifier_name":"genetics","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000235","qualifier_name":"genetics","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D000071158","descriptor_name":"Leucine-Rich Repeat Serine-Threonine Protein Kinase-2","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D006801","descriptor_name":"Humans","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D006801","descriptor_name":"Humans","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D006801","descriptor_name":"Humans","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D009154","descriptor_name":"Mutation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":true},{"descriptor_ui":"D009154","descriptor_name":"Mutation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":true},{"descriptor_ui":"D009154","descriptor_name":"Mutation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":true},{"descriptor_ui":"D011485","descriptor_name":"Protein Binding","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D011485","descriptor_name":"Protein Binding","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D011485","descriptor_name":"Protein Binding","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D011487","descriptor_name":"Protein Conformation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D011487","descriptor_name":"Protein Conformation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D011487","descriptor_name":"Protein Conformation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D013816","descriptor_name":"Thermodynamics","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D013816","descriptor_name":"Thermodynamics","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D013816","descriptor_name":"Thermodynamics","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D047428","descriptor_name":"Protein Kinase Inhibitors","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D047428","descriptor_name":"Protein Kinase Inhibitors","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D047428","descriptor_name":"Protein Kinase Inhibitors","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D047428","descriptor_name":"Protein Kinase Inhibitors","qualifier_ui":"Q000494","qualifier_name":"pharmacology","is_major_topic":true},{"descriptor_ui":"D047428","descriptor_name":"Protein Kinase Inhibitors","qualifier_ui":"Q000494","qualifier_name":"pharmacology","is_major_topic":true},{"descriptor_ui":"D047428","descriptor_name":"Protein Kinase Inhibitors","qualifier_ui":"Q000494","qualifier_name":"pharmacology","is_major_topic":true},{"descriptor_ui":"D047428","descriptor_name":"Protein Kinase Inhibitors","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D047428","descriptor_name":"Protein Kinase Inhibitors","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D047428","descriptor_name":"Protein Kinase Inhibitors","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D056004","descriptor_name":"Molecular Dynamics Simulation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D056004","descriptor_name":"Molecular Dynamics Simulation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D056004","descriptor_name":"Molecular Dynamics Simulation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false}],"locations_count":2,"locations":[{"id":"doi:10.1021/acs.jcim.6c00156","is_oa":false,"landing_page_url":"https://doi.org/10.1021/acs.jcim.6c00156","pdf_url":null,"source":{"id":"https://openalex.org/S167262187","display_name":"Journal of Chemical Information and Modeling","issn_l":"1549-9596","issn":["1549-9596","1549-960X"],"is_oa":false,"is_in_doaj":false,"is_core":true,"host_organization":"https://openalex.org/P4310320006","host_organization_name":"American Chemical Society","host_organization_lineage":["https://openalex.org/P4310320006"],"host_organization_lineage_names":["American Chemical Society"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Chemical Information and Modeling","raw_type":"journal-article"},{"id":"pmid:42130234","is_oa":false,"landing_page_url":"https://pubmed.ncbi.nlm.nih.gov/42130234","pdf_url":null,"source":{"id":"https://openalex.org/S4306525036","display_name":"PubMed","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of chemical information and modeling","raw_type":"Journal Article"}],"best_oa_location":null,"sustainable_development_goals":[{"display_name":"Affordable and clean energy","id":"https://metadata.un.org/sdg/7","score":0.6365088820457458}],"awards":[],"funders":[],"has_content":{"pdf":false,"grobid_xml":false},"content_urls":null,"referenced_works_count":62,"referenced_works":["https://openalex.org/W1611134798","https://openalex.org/W1970687029","https://openalex.org/W1971275758","https://openalex.org/W1975708211","https://openalex.org/W1976161355","https://openalex.org/W1976499671","https://openalex.org/W1986614779","https://openalex.org/W1993177346","https://openalex.org/W2000579654","https://openalex.org/W2003883601","https://openalex.org/W2011301426","https://openalex.org/W2015688756","https://openalex.org/W2017162768","https://openalex.org/W2029667189","https://openalex.org/W2035266068","https://openalex.org/W2035687084","https://openalex.org/W2057806291","https://openalex.org/W2059844062","https://openalex.org/W2065283382","https://openalex.org/W2073623394","https://openalex.org/W2074631079","https://openalex.org/W2078474072","https://openalex.org/W2088765009","https://openalex.org/W2103945336","https://openalex.org/W2122072833","https://openalex.org/W2124681346","https://openalex.org/W2134829539","https://openalex.org/W2147993766","https://openalex.org/W2205544783","https://openalex.org/W2253950023","https://openalex.org/W2404280981","https://openalex.org/W2550736838","https://openalex.org/W2619609791","https://openalex.org/W2768016303","https://openalex.org/W2795590254","https://openalex.org/W2885615510","https://openalex.org/W2952530396","https://openalex.org/W2960012086","https://openalex.org/W3008003211","https://openalex.org/W3034806025","https://openalex.org/W3035965352","https://openalex.org/W3046751266","https://openalex.org/W3081141890","https://openalex.org/W3098923693","https://openalex.org/W3150635270","https://openalex.org/W3158032220","https://openalex.org/W3171048111","https://openalex.org/W3207815411","https://openalex.org/W3209226002","https://openalex.org/W4221052422","https://openalex.org/W4286587504","https://openalex.org/W4361282008","https://openalex.org/W4385850494","https://openalex.org/W4387440676","https://openalex.org/W4389233086","https://openalex.org/W4389452875","https://openalex.org/W4389729301","https://openalex.org/W4392157049","https://openalex.org/W4399259105","https://openalex.org/W4407407380","https://openalex.org/W4408232209","https://openalex.org/W4412181522"],"related_works":[],"abstract_inverted_index":{"Parkinson's":[0],"disease":[1],"(PD),":[2],"the":[3,31,37,41,51,59,62,73,81,86,95,105,125,136,143,149,163,167,170,192,196,204,207,217,227,231,276],"second":[4],"most":[5],"common":[6],"age-related":[7],"neurodegenerative":[8],"disorder":[9],"worldwide,":[10],"is":[11,21],"associated":[12],"with":[13,282],"mutations":[14,71],"in":[15,61,100,128,177,216],"several":[16],"genes,":[17],"one":[18],"of":[19,36,85,94,195,206,266],"which":[20],"LRRK2":[22],"(leucine-rich":[23],"repeat":[24],"kinase":[25,188],"2).":[26],"Despite":[27],"cryo-EM":[28],"structures":[29],"elucidating":[30],"active":[32,150,179,198,212,233],"and":[33,44,88,92,116,158,175,239,260,268],"inactive":[34],"architectures":[35],"wild":[38],"type":[39],"(WT),":[40],"regulatory":[42],"mechanisms":[43],"intermediate":[45],"conformational":[46,74,214],"states":[47],"(INTs)":[48],"that":[49,226,275],"facilitate":[50],"transition":[52,165],"between":[53],"these":[54],"forms,":[55],"as":[56,58],"well":[57],"distinctions":[60],"G2019S":[63,137,171,197],"mutant,":[64],"remain":[65],"unclear.":[66],"Here,":[67],"we":[68,202],"elucidated":[69],"how":[70],"reshape":[72],"dynamics":[75,78],"through":[76],"molecular":[77],"simulations,":[79],"highlighting":[80,235],"salt":[82],"bridge":[83],"contributions":[84],"E1920-R2026":[87,269],"K1906-D2017":[89],"residue":[90,270],"pairs":[91],"fluctuations":[93],"activation":[96,140,174],"loop":[97],"(A-loop)":[98],"lid":[99],"stabilizing":[101],"specific":[102],"states.":[103],"Furthermore,":[104],"reconstructed":[106],"two-dimensional":[107,248],"Well-Tempered":[108],"Metadynamics":[109],"(2D":[110],"WT-MetaD)":[111],"free-energy":[112,223],"landscape":[113],"along":[114],"A-loop":[115],"K1906-E1920":[117,267],"coordinates":[118],"revealed":[119,130,274],"two":[120,280],"distinct":[121],"activation/inactivation":[122],"pathways.":[123],"Interestingly,":[124],"inactivation":[126],"pathway":[127],"WT":[129],"a":[131,182],"metastable":[132],"\"semi-open\"":[133],"state,":[134,234],"while":[135],"mutation":[138,172],"favored":[139],"by":[141],"decreasing":[142],"inactive-to-active":[144],"energy":[145,161],"barrier;":[146],"however,":[147],"once":[148],"state":[151,213],"was":[152],"formed,":[153],"it":[154],"became":[155],"comparatively":[156],"stable":[157],"required":[159],"more":[160],"for":[162,185,211],"active-to-inactive":[164],"than":[166],"WT.":[168,246],"Thus,":[169],"facilitated":[173],"remained":[176],"its":[178,186,236],"form,":[180],"providing":[181],"mechanistic":[183],"basis":[184],"uncontrolled":[187],"hyperactivity.":[189],"To":[190],"reinforce":[191],"MetaD-derived":[193],"stability":[194],"conformation":[199],"over":[200],"WT,":[201],"assessed":[203],"binding":[205,222,237],"type-I":[208],"inhibitor":[209,242],"LRRK2-IN-1":[210],"rearrangements":[215,259],"ligand-bound":[218],"state.":[219],"The":[220,272],"absolute":[221],"consistently":[224],"showed":[225,252],"ligand":[228],"preferentially":[229],"stabilizes":[230],"mutant":[232,277],"affinity":[238],"modestly":[240],"increased":[241],"potency,":[243],"relative":[244],"to":[245],"Finally,":[247],"Umbrella":[249],"Sampling":[250],"(2D-US)":[251],"apo-state":[253],"transitions":[254],"arising":[255],"from":[256],"DYGI":[257],"(D2017-Y2018-G2019-I2020)":[258],"\u03b1C-helix":[261],"coupling":[262],"via":[263],"COM":[264],"distances":[265],"pairs.":[271],"results":[273],"(G2019S)":[278],"follows":[279],"routes":[281],"four":[283],"INTs.":[284]},"counts_by_year":[],"updated_date":"2026-07-18T07:39:51.176621","created_date":"2026-05-15T00:00:00"}
