caa a22 4500 605513163 CHVBK 20210128100659.0 cr unu---uuuuu 210128e20150501xx s 000 0 eng 10.1007/s00894-015-2673-6 doi (NATIONALLICENCE)springer-10.1007/s00894-015-2673-6 How Y357F, Y276F mutants affect the methylation activity of PRDM9: QM/MM MD and free energy simulations [Elektronische Daten] [Yuzhuo Chu, Lu Sun, Shijun Zhong] Histone methyltransferase PRDM9 catalyzes the methylation of H3K4me2 (histone 3 dimethylated lysine 4) to H3K4me3 (histone 3 trimethylated lysine 4) by transferring the methyl group from S-adenosyl methionine (AdoMet). PRDM9 is the major determinant of the meiotic recombination hotspot and the enrichment of H3K4me3 at the hotspot defines the initiation site of meiotic recombination. In PRDM9, two conserved tyrosine residues Tyr357 and Tyr276 surrounding the amino group of the substrate lysine may influence the methylation activity through hydrogen bond interactions with AdoMet or the substrate lysine. In this study, quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations were performed to reveal the methylation processes catalyzed by wild type PRDM9, its Y357F, and Y276F mutants, respectively. The different roles of Tyr357 and Tyr276 in the methylation activity of PRDM9 were also investigated and compared. The calculated free energy barriers of the methyl transfers suggest that the Y276F mutation decreases the catalytic activity of the methyl transfer, while the Y357F mutation does not change the catalytic activity of the methyl transfer. The reactant complex conformations generated in the QM/MM MD simulations show that the reactive configuration can be formed in the Y357F mutant but not in the Y276F mutant. Springer-Verlag Berlin Heidelberg, 2015 Catalytic activity nationallicence Histone methyltransferase nationallicence Methylation activity nationallicence QM/MM MD and free energy simulations nationallicence Reactive complex nationallicence Chu Yuzhuo School of Life Science and Biotechnology, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, Liaoning Province, China aut Sun Lu School of Life Science and Biotechnology, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, Liaoning Province, China aut Zhong Shijun School of Life Science and Biotechnology, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, Liaoning Province, China aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/5(2015-05-01), 1-10 1610-2940 21:5<1 2015 21 894 https://doi.org/10.1007/s00894-015-2673-6 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2673-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Chu Yuzhuo School of Life Science and Biotechnology, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, Liaoning Province, China aut NATIONALLICENCE 700 1- Sun Lu School of Life Science and Biotechnology, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, Liaoning Province, China aut NATIONALLICENCE 700 1- Zhong Shijun School of Life Science and Biotechnology, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, Liaoning Province, China aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/5(2015-05-01), 1-10 1610-2940 21:5<1 2015 21 894