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DNA Deformation Exerted by Regulatory DNA-Binding Motifs in Human Alkyladenine DNA Glycosylase Promotes Base Flipping.
Wang, Lingyan; Xi, Kun; Zhu, Lizhe; Da, Lin-Tai.
Afiliación
  • Wang L; Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
  • Xi K; Warshel Institute for Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong 518172, P. R. China.
  • Zhu L; Warshel Institute for Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong 518172, P. R. China.
  • Da LT; Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
J Chem Inf Model ; 62(13): 3213-3226, 2022 07 11.
Article en En | MEDLINE | ID: mdl-35708296
ABSTRACT
Human alkyladenine DNA glycosylase (AAG) is a key enzyme that corrects a broad range of alkylated and deaminated nucleobases to maintain genomic integrity. When encountering the lesions, AAG adopts a base-flipping strategy to extrude the target base from the DNA duplex to its active site, thereby cleaving the glycosidic bond. Despite its functional importance, the detailed mechanism of such base extrusion and how AAG distinguishes the lesions from an excess of normal bases both remain elusive. Here, through the Markov state model constructed on extensive all-atom molecular dynamics simulations, we find that the alkylated nucleobase (N3-methyladenine, 3MeA) everts through the DNA major groove. Two key AAG motifs, the intercalation and E131-N146 motifs, play active roles in bending/pressing the DNA backbone and widening the DNA minor groove during 3MeA eversion. In particular, the intercalated residue Y162 is involved in buckling the target site at the early stage of 3MeA eversion. Our traveling-salesman based automated path searching algorithm further revealed that a non-target normal adenine tends to be trapped in an exo site near the active site, which however barely exists for a target base 3MeA. Collectively, these results suggest that the Markov state model combined with traveling-salesman based automated path searching acts as a promising approach for studying complex conformational changes of biomolecules and dissecting the elaborate mechanism of target recognition by this unique enzyme.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: ADN Glicosilasas Límite: Humans Idioma: En Revista: J Chem Inf Model Asunto de la revista: INFORMATICA MEDICA / QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: ADN Glicosilasas Límite: Humans Idioma: En Revista: J Chem Inf Model Asunto de la revista: INFORMATICA MEDICA / QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: China