The pandemic of COVID-19 severe acute respiratory syndrome, which was fatal for millions of people worldwide, triggered the race to understand in detail the molecular mechanisms of this disease. In this work, the differences of interactions between the SARS-CoV/SARS-CoV-2 Receptor binding domain (RBD) and the human Angiotensin Converting Enzyme 2 (ACE2) receptor were studied using in silico tools. Our results show that SARS-CoV-2 RBD is more stable and forms more interactions with ACE2 than SARS-CoV. At its interface, three stable binding patterns are observed and named red-K31, green-K353 and blue-M82 according to the central ACE2 binding residue. In SARS-CoV instead, only the first two binding patches are persistently formed during the MD simulation. Our MM/GBSA calculations indicate the binding free energy difference of about 2.5 kcal/mol between SARS-CoV-2 and SARS-CoV which is compatible with the experiments. The binding free energy decomposition points out that SARS-CoV-2 RBD–ACE2 interactions of the red-K31 ($$-23.5~\pm ~0.2~kcal/mol$$ - 23.5 ± 0.2 k c a l / m o l ) and blue-M82 ($$-9.1~\pm ~0.1~kcal/mol$$ - 9.1 ± 0.1 k c a l / m o l ) patterns contribute more to the binding affinity than in SARS-CoV ($$-1.8~\pm ~0.02~kcal/mol$$ - 1.8 ± 0.02 k c a l / m o l for red-K31), while the contribution of the green-K353 pattern is very similar in the two strains ($$-17.8~\pm ~0.2~kcal/mol$$ - 17.8 ± 0.2 k c a l / m o l and $$-22.7~\pm ~0.1~kcal/mol$$ - 22.7 ± 0.1 k c a l / m o l for SARS-CoV-2 and SARS-CoV, respectively). Five groups of mutations draw our attention at the RBD–ACE2 binding interface, among them, the mutation –PPA469-471/GVEG482-485 has the most important and favorable impact on SARS-CoV-2 binding to the ACE2 receptor. These results, highlighting the molecular differences in the binding between the two viruses, contribute to the common knowledge about the new corona virus and to the development of appropriate antiviral treatments, addressing the necessity of ongoing pandemics.

The outbreak of the 2019-nCoV coronavirus causing severe acute respiratory syndrome which can be fatal, especially in elderly population, has been declared a pandemic by the World Health Organization. Many biotechnology laboratories are rushing to develop therapeutic antibodies and antiviral drugs for treatment of this viral disease. The viral CoV spike (S) glycoprotein is one of the main targets for pharmacological intervention. Its receptor-binding domain (RBD) interacts with the human ACE2 receptor ensuring the entry of the viral genomes into the host cell. In this work, we report on the differences in the binding of the RBD of the previous coronavirus SARS-CoV and of the newer 2019-nCoV coronavirus to the human ACE2 receptor using atomistic molecular dynamics techniques. Our results show major mutations in the 2019-nCoV RBD with respect to the SARS-CoV RBD occurring at the interface of RBD-ACE2 complex.These mutations make the 2019-nCoV RBD protein backbone much more flexible, hydrophobic interactions are reduced and additional polar/charged residues appear at the interface. We observe that higher flexibility of the 2019-nCoV RBD with respect to the SARS-CoV RBD leads to a bigger binding interface between the 2019-nCoV RBD and ACE2 and to about 20% more contacts between them in comparison with SARS-CoV.Taken together, the 2019-nCoV RBD shows more stable binding interface and higher binding affinity for the ACE2 receptor. The mutations not only stabilize the binding interface, they also lead to overall more stable 2019-nCoV RBD protein structure, even far from the binding interface. Our results on the molecular differences in the binding between the two viruses can provide important inputs for development of appropriate antiviral treatments of the new viruses, addressing the necessity of ongoing pandemics.

Gout is an extremely painful form of inflammatory arthritis, caused by the formation of monosodium urate (MSU) crystals in the joints. MSU crystals are one of the triggers for the activation of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome (NACHT, LRR and PYD domains-containing protein), which in turn induces caspase-1 activation and a nonspecific immune responses that cause inflammation. Further structural studies and ligand designs are needed to block the interaction of NLRP3 with MSU or allow the interaction without activating caspase-1. This would facilitate the screening of new drugs for the treatment of gout. Using computational methods for homology modeling and molecular dynamics simulations, the structural model of mouse NLRP3 protein with its domains, three potential structural models were consistently constructed and tested to find the most stable structural model. Adenosine triphosphate (ATP) — an activator of NACHT (the central domain of mouse NLRP3 protein) — was docked and simulated. Ligand effects to activate as well as limit this protein were analyzed. This study provides insights to deeper understanding about gout development pathway via the NLRP3 protein.

Since the discovery of the role of NLRP3 in microbial infection in 2001, many studies have shown that NLRP3 play a key role in causing many mammal acute and chronic diseases. However, a full understanding of the mechanism of NLRP3 activation is still lacking. Our previous theoretical work and experimental evidence show the role of ATP in interacting with and activating the NATCH region of NLRP3. In this study, we continue to use bioinformatics and molecular dynamic (MD) simulation to evaluate the competitive impact of the interaction the ligand ATP and colchicine (COL) with this NACHT protein. The later ligand is a medication to treat gout attacks. Our results show that COL bind stably to the ATP binding pocket of mice NACHT domain with high numbers of hydrophobic and van der Waals interactions, while hydrogen bond and electrostatic interactions are important types of contact for keeping ATP at its NACHT pocket. Our results assist in building in-silico screening model for natural compounds with pharmacological effects to NLRP3 similar to colchicine with few side effects. In addition, this work helps to better understand the balance between this inflammasome activation and inhibition, which will help in the improvement and development of new therapies for related diseases.