Superkomputer: Zastosowania

We plan to continue our investigations on the molecular mechanisms of the interaction of the two SARS-CoV-2 proteins ORF6 and Nsp13 with the proteins of the infected cells (primarily, RAE1, RAE1-NUP98, and TBK1) aiming at identifying or designing selective viral-protein inhibitors. Earlier, we have developed a 3D model of the viral protein ORF6 in an aqueous environment, as well as in two model membranes, similar in composition to the membranes of the Golgi apparatus and the endoplasmic reticulum in cells. The results of our MD simulations are in excellent agreement with the recently published crystallographic structure of the complex of NUP98-RAE1 and the C-terminal peptide of ORF6 of SARS-CoV and SARS-CoV-2 viruses. They also gave us a valuable hint in searching for inhibitors of this most toxic SARS-CoV-2 protein. Our preliminary small-scale simulations indicate the ability of two biomolecules to take over this role. We want to conduct long-scale simulations to confirm this hypothesis.
We want to proceed with our computational studies on the interaction between SARS-CoV-2 helicase NSP13 и the cell protein TBK1, our initial model being based on the analysis of the SARS-CoV-2 replicase-transcriptase complex and the structural similarity between TBK1 and the viral NSP8. The potential binding pocket here has a complicated ion-dependent geometry and proposing a prospective ligand requires a multitude of long-scale simulations.
Stepping on our previous results on the peptide-membrane interaction energetics, we aim at validating our hypothesis about the AMPs mechanism of action and the role of the non-cationic peptides in the original natural substances (such as the snail mucus). In addition, we want to understand the role topology plays for the biological activity of these peptides on the specific example of cyclotides, when used as scaffolds for grafting onto them biologically active molecules to achieve or amplify certain action.
We shall keep (mainly) to all-atom approach, but where suitable, we shall use both all-atom and coarse-grain approaches. Specifically, we shall probe the new functionalities of the UNRES for modelling dynamic disulfide bridges that is essential in cyclotides design and simulations. The investigated systems range from several hundred thousand to a million atoms and require significant computational resources.