Molecular dynamics simulation study reveals polar nature of pathogenic mutations responsible for stabilizing active conformation of kinase domain in leucine-rich repeat kinase II
The kinase domain of LRRK2 is increasingly gaining attention as a promising therapeutic target due to pathogenic mutation leading to development of Parkinson’s disease. Mutation in G2019S and I2020T increases the kinase activity, while A2016T mutation causes drug resistance. Increased kinase activity of LRRK2 has been associated with deposition of tau and α-synuclein proteins. However, mechanism responsible for increase in activity due to mutation is not known. In the present study, extensive molecular dynamics study has been performed on both wild and mutant homology models of DYG-In (active) conformation of the kinase domain of LRRK2 in the absence/presence of ATP at the active site to study the behavior of DYG loop. In absence of ATP, it is observed that G2019S and I2020T mutants stabilize DYG loop by increasing formation of hydrogen bond with neighboring residues, mainly with GLU 1920 and ILE 1991, respectively. In ATP-kinase complex, DYG loop also increases hydrogen bonding with neighboring residues in mutant LRRK2. The study indicates that polar side chain of mutated residues increases the polarity of DYG loop, causing an increase in hydrogen bonding with neighboring residues to stabilize the active conformation of kinase domain in LRRK2. The binding free energy of ATP is found to be higher in mutated kinase as compared to wild, due to more stable kinase domain.
KeywordsParkinson’s disease DYG loop Kinase domain LRRK2 MM-GBSA Molecular dynamics
The authors would like to thank the University Grant Commission (UGC), New Delhi, and University with Potential for Excellence (UPE) Phase-II, University of Calcutta, Kolkata, India, for financial assistance of the project. KR thanks the UGC New Delhi for financial assistance under the UPE-II scheme.
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Conflict of interest
The authors declare that they have no conflict of interest.
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