MD and QM/MM Study of the Quaternary HutP Homohexamer Complex with mRNA, L-Histidine Ligand, and Mg2+

POKORNÁ, Pavlína, Miroslav KREPL, Holger KRUSE a Jiří ŠPONER. MD and QM/MM Study of the Quaternary HutP Homohexamer Complex with mRNA, L-Histidine Ligand, and Mg2+. Journal of Chemical Theory and Computation. Washington DC: American Chemical Society, 2017, roč. 13, č. 11, s. 5658-5670. ISSN 1549-9618. Dostupné z: https://dx.doi.org/10.1021/acs.jctc.7b00598.

Základní údaje

Originální název

MD and QM/MM Study of the Quaternary HutP Homohexamer Complex with mRNA, L-Histidine Ligand, and Mg2+

Autoři

POKORNÁ, Pavlína, Miroslav KREPL, Holger KRUSE a Jiří ŠPONER

Vydání

Journal of Chemical Theory and Computation, Washington DC, American Chemical Society, 2017, 1549-9618

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Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.399

DOI

http://dx.doi.org/10.1021/acs.jctc.7b00598

UT WoS

000415911800042

Štítky

ne MU, RIV ne

Příznaky

Mezinárodní význam, Recenzováno

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Anotace

V originále

The HutP protein from B. subtilis regulates histidine metabolism by interacting with an antiterminator mRNA hairpin in response to the binding of L-histidine and Mg2+. We studied the functional ligand-bound HutP hexamer complexed with two mRNAs using all-atom microsecond-scale explicit-solvent MD simulations performed with the Amber force fields. The experimentally observed protein-RNA interface exhibited good structural stability in the simulations with the exception of some fluctuations in an unusual adenine-threonine interaction involving two closely spaced H-bonds. We further investigated this interaction by comparing QM/MM and MM optimizations, using the QM region comprising almost 350 atoms described at the DFT-D3 level. The QM/MM method clearly improved the adenine-threonine interaction compared to MM, especially when the X H bond lengths were frozen during the MM optimization to mimic the use of SHAKE in the MD simulations. Thus, both the MM approximation and the use of SHAKE can compromise the description of H-bonds at protein RNA interfaces. The simulations also revealed a notable Mg2+-parameter dependence in the behavior of the ligand-binding pocket (LBP). With the SPC/E water model, the 12-6 Aqvist and Li&Merz parameters provided an entirely stable LBP structure, but the 12-6 Allner and 12-6-4 Li&Merz parametrizations resulted in a progressive loss of direct nitrogen Mg2+ LBP coordination. The Aliner and Li&Merz 12-6 parametrizations were also tested with the TIP3P water model; the LBP was destabilized in both cases. This illustrates the difficulty of consistently describing different Mg2+ interactions using nonpolarizable force fields. Overall, the simulations support the hypothesis that HutP protein becomes fully structured upon ligand binding. Subsequent RNA binding does not affect the protein structure, in keeping with the mechanism inferred from experimental structures.