Naslov
DNA Methyltransferase Dnmt1: regulation of substrate selectivity

Autori
Nikolić, Patrik ; Miletić, Vedran, Svedružić, Željko M.

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
6th OEGMBT Annual Meeting 2014 Abstract Book / - Beč, 2014

Skup
6th OEGMBT Annual Meeting 2014

Mjesto i datum
Beč, Austrija, 15.09.2014. - 18.09.2014

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
DNA methyltransferase; Dnmt1; QM/MM; molecular dynamics; GROMACS; CUDA

Sažetak
DNA methylation is a fundamental mechanism in functional organization of the human genome. Accordingly, DNA methyltransferase 1, Dnmt1, has been unsuccessfully targeted in different drug-design efforts for the last 30 years. Most of those failures can be attributed to inadequate understanding of dynamic structural changes that regulate Dnmt1 activity and its interaction with other molecules. Using a combination of different QM/MM/MD methods we have identified several novel mechanism-based inhibitors by exploiting dynamic structural changes that control interactions between Dnmt1 and its substrates. Typical simulation used 500000 steps in total duration of 1 nsec on GPU-accelerated version of GROMACS software package on NVIDIA CUDA-enabled GPUs. The simulations identified substrate analogues that have preserved key interactions with the enzyme and showed that solvent molecules are crucial for interactions between Dnmt1 with its cofactor. Substrate is positioned in the active site by a dynamic active site loop that acts as substrate lock-and-press mechanism just as earlier indicated in the experimental studies. QM studies identified several substrate analogues that have the highest reactivity towards active site cysteine.

Izvorni jezik
Engleski

Znanstvena područja
Računarstvo, Farmacija, Biotehnologija

POVEZANOST RADA