Recognition of N6-Methyladenosine by the YTHDC1 YTH Domain Studied by Molecular Dynamics and NMR Spectroscopy: The Role of Hydration

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Publikace nespadá pod Ústav výpočetní techniky, ale pod Přírodovědeckou fakultu. Oficiální stránka publikace je na webu muni.cz.

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KREPL Miroslav DAMBERGER Fred Franz VON SCHROETTER Christine THELER Dominik POKORNÁ Pavlína ALLAIN Šponer H.-T. ŠPONER Jiří

Rok publikování 2021
Druh Článek v odborném periodiku
Časopis / Zdroj Journal of Physical Chemistry B
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
www https://doi.org/10.1021/acs.jpcb.1c03541
Doi http://dx.doi.org/10.1021/acs.jpcb.1c03541
Klíčová slova Genetics; Monomers; Molecules; Protein structure; Chemical calculations
Popis The YTH domain of YTHDC1 belongs to a class of protein "readers", recognizing the N6-methyladenosine (m(6)A) chemical modification in mRNA. Static ensemble-averaged structures revealed details of N6-methyl recognition via a conserved aromatic cage. Here, we performed molecular dynamics (MD) simulations along with nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC) to examine how dynamics and solvent interactions contribute to the m(6)A recognition and negative selectivity toward an unmethylated substrate. The structured water molecules surrounding the bound RNA and the methylated substrate's ability to exclude bulk water molecules contribute to the YTH domain's preference for m(6)A. Intrusions of bulk water deep into the binding pocket disrupt binding of unmethylated adenosine. The YTHDC1's preference for the 5'-Gm(6)A-3' motif is partially facilitated by a network of water-mediated interactions between the 2amino group of the guanosine and residues in the m(6)A binding pocket. The 5'-Im(6)A-3' (where I is inosine) motif can be recognized too, but disruption of the water network lowers affinity. The D479A mutant also disrupts the water network and destabilizes m(6)A binding. Our interdisciplinary study of the YTHDC1 protein-RNA complex reveals an unusual physical mechanism by which solvent interactions contribute toward m(6)A recognition.
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