Összes szerző

Lountos George T.

az alábbi absztraktok szerzői között szerepel:

Hoffka Gyula
Crystallographic and molecular dynamics simulations shed light on the self-inactivated conformation of the Venezuelan equine encephalitis virus (VEEV) protease

Aug 29 - kedd

15:30 – 17:00

I. Poszterszekció

P12

Crystallographic and molecular dynamics simulations shed light on the self-inactivated conformation of the Venezuelan equine encephalitis virus (VEEV) protease

Gyula Hoffka1,2, George T. Lountos3, József Tőzsér1 and János András Mótyán1

1 University of Debrecen, Faculty of Medicine, Department of Biochemistry and Molecular Biology, Laboratory of Retroviral Biochemistry

2 University of Debrecen, Doctoral School of Molecular Cell and Immune Biology

3 Frederick National Laboratory for Cancer Research, Basic Science Program

The application of computational simulations in molecular biology allows us to examine a wide range of properties of enzymes, which would otherwise be challenging using experimental methods. Molecular dynamics are exceptionally useful to study conformational landscapes, substrate binding patterns, as well as interaction networks.

The Venezuelan equine encephalitis virus (VEEV) is responsible for causing mild to severe disease in both humans and livestock. The non-structural protein 2 protease (nsP2pro) of VEEV is considered as a drug target due to its crucial role in the viral life-cycle. Therefore, investigation of this viral protein may provide valuable information for structure-based drug design.

We aimed to study the structure of VEEV nsP2pro using both in vitro and in silico approaches. The structure, containing the wild-type N475 N-terminal residue at the active site, was determined experimentally at high resolution (1.46 Å), using X-ray crystallography [1]. The protein exhibited an unexpected conformation wherein the N-terminus mimics substrate binding. This self-inactivated conformation was previously observed only for a N475A mutant enzyme.

To compare the active and inactive conformers, we have used the Amber16 software for molecular dynamics simulations. We investigated the dynamic hydrogen bond networks at the active site, and compared the differences between the dynamic properties of the active and self-inactivated conformers as well as between the N475 and A475 containing variants. The comparison sheds light on the interactions that are crucial to the stabilization of the conformers.

Project no. TKP2021-EGA-20 (Biotechnology) has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP2021-EGA funding scheme. We acknowledge KIFÜ for awarding us access to resource based in Hungary.

[1] Hoffka G, Lounto GT, Needle D, Wlodawer A, Waugh DS, Tőzsér J, Mótyán JA (2023) J Mol Biol 435:168012