In Silico Studies of The Human IAPP In Presence of Osmolytes

The human islet amyloid polypeptide or amylin is secreted along with insulin by pancreatic islets. Under the drastic environmental conditions, amylin can aggregate to form amyloid fibrils. This amyloid plaque of hIAPP in the pancreatic cells is the cause of Type II diabetes. Early stages of amylin aggregates are more cytotoxic than the matured fibrils. Here, we have used the all-atom molecular dynamic simulation to see the effect of water, TMAO, urea and urea:TMAO having ratio 2:1 of different concentrations on the amylin protein. Our study suggest that the amylin protein forms β-sheets in its monomeric form and may cause the aggregation of protein through the residue 13-17 and the C-terminal region. α-helical content of protein increases with an increase in TMAO concentration by decreasing the SASA value of protein, increase in intramolecular hydrogen bonds and on making the short range hydrophobic interactions. Electrostatic potential surfaces shows that hydrophobic groups are buried and configurational entropy of backbone atoms is lesser in presence of TMAO, whereas opposite behaviour is obtained in case of urea. Counteraction effect of TMAO using Kast model towards urea is also observed in ternary solution of urea:TMAO.

Protein structure prediction using AI and quantum computers

This work seeks to combine the combined advantage of leveraging these emerging areas of Artificial Intelligence and quantum computing in applying it to solve the specific biological problem of protein structure prediction using Quantum Machine Learning algorithms. The CASP dataset from ProteinNet was downloaded which is a standardized data set for machine learning of protein structure. Its large and standardized dataset of PDB entries contains the coordinates of the backbone atoms, corresponding to the sequential chain of N, C_alpha, and C' atoms. This dataset was used to train a quantum-classical hybrid Keras deep neural network model to predict the structure of the proteins. To visually qualify the quality of the predicted versus the actual protein structure, protein contact maps were generated with the experimental and predicted protein structure data and qualified. Therefore this model is recommended for the use of protein structure prediction using AI leveraging the power of quantum computers. The code is provided in the following Github repository https://github.com/bengeof/Protein-structure-prediction-using-AI-and-quantum-computers.

Backbone chemical shift spectral assignments of SARS coronavirus-2 non-structural protein nsp9

As part of an International consortium aiming at the characterization by NMR of the proteins of the SARS-CoV-2 virus, we have obtained the virtually complete assignment of the backbone atoms of the non-structural protein nsp9. This small (12 kDa) protein is encoded by ORF1a, binds to RNA and seems to be essential for viral RNA synthesis. The crystal structures of the SARS-CoV-2 protein and other homologues suggest that the protein is dimeric as also confirmed by analytical ultracentrifugation and dynamic light scattering. Our data constitute the prerequisite for further NMR-based characterization, and provide the starting point for the identification of small molecule lead compounds that could interfere with RNA binding and prevent viral replication.

Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease

The use of antiretroviral drugs is accompanied by the emergence of HIV-2 resistances. Thus, it is important to elucidate the mechanisms of resistance to antiretroviral drugs. Here, we propose a structural analysis of 31 drug-resistant mutants of HIV-2 protease (PR2) that is an important target against HIV-2 infection. First, we modeled the structures of each mutant. We then located structural shifts putatively induced by mutations. Finally, we compared wild-type and mutant inhibitor-binding pockets and interfaces to explore the impacts of these induced structural deformations on these two regions. Our results showed that one mutation could induce large structural rearrangements in side-chain and backbone atoms of mutated residue, in its vicinity or further. Structural deformations observed in side-chain atoms are frequent and of greater magnitude, that confirms that to fight drug resistance, interactions with backbone atoms should be favored. We showed that these observed structural deformations modify the conformation, volume, and hydrophobicity of the binding pocket and the composition and size of the PR2 interface. These results suggest that resistance mutations could alter ligand binding by modifying pocket properties and PR2 stability by impacting its interface. Our results reinforce the understanding of the effects of mutations that occurred in PR2 and the different mechanisms of PR2 resistance.

Steric vs Electronic Effects: A New Look into Stability of Diastereomers, Conformers and Constitutional Isomers

<div>A quantum chemical investigation of the stability of compounds with identical formulas was carried out on 23 classes of halogenated compounds made of H, F, Cl, Br, I, C, N, P, O and S atoms. The prevalence of formula in which its Z configuration, gauche conformation and meta isomer are the most stable forms is calculated and discussed. The prevalence data shows that in compounds made of carbon backbones, the electronic effect is weaker than the steric effect. The electronic factor is more important as the backbone atoms are replaced with atoms on the right and upper part of the periodic table.</div>

Steric vs Electronic Effects: A New Look into Stability of Diastereomers, Conformers and Constitutional Isomers

<div>A quantum chemical investigation of the stability of compounds with identical formulas was carried out on 23 classes of halogenated compounds made of H, F, Cl, Br, I, C, N, P, O and S atoms. The prevalence of formula in which its Z configuration, gauche conformation and meta isomer are the most stable forms is calculated and discussed. The prevalence data shows that in compounds made of carbon backbones, the electronic effect is weaker than the steric effect. The electronic factor is more important as the backbone atoms are replaced with atoms on the right and upper part of the periodic table.</div>

Synthesis and evaluation of potent human immunodeficiency virus 1 protease inhibitors with epimeric isopropanol as novel P1′ ligands

Aim: HIV-1 protease inhibitors regimens suffered from a number of drawbacks, among which, the most egregious issue was the growing emergence of drug-resistant strains. Materials & methods: The design strategy of maximizing the protease active site interactions with the inhibitor, especially promoting extensive hydrogen bonding with the protein backbone atoms, might be in favor of combating drug resistance. A series of HIV-1 protease inhibitors that incorporated enantiomeric isopropanols as the P1′ ligands in combination with phenols as the P2 ligands were reported herein. Results: A number of inhibitors displayed potent protease enzyme inhibition activity. In particular, inhibitor 14c showed comparable potency as darunavir with IC50 value of 1.91 nM and activity against darunavir-resistant HIV-1 variants. Conclusion: The new kind of HIV-1 protease inhibitors deserves further study.

Anisotropic Hydrolysis Susceptibility in Deformed Polydimethylsiloxanes

<div>Chemical reactions involving the polydimethylsiloxane (PDMS) backbone can induce significant network rearrangements and ultimately degrade macro-scale mechanical properties of silicone components. Using two levels of quantum chemical theory, we identify a possible electronic driver for chemical susceptibility in strained PDMS chains and explore the complicated interplay between hydrolytic chain scissioning reactions, mechanical deformations of the backbone, water attack vector, and chain mobility. Density functional theory (DFT) calculations reveal that susceptibility to hydrolysis varies significantly with the vector for water attacks on silicon backbone atoms, which matches strain-induced anisotropic changes in the backbone electronic structure. Efficient semiempirical density functional tight binding (DFTB) calculations are shown to reproduce DFT predictions for select reaction pathways and facilitate more exhaustive explorations of configuration space. We show that concerted strains of the backbone must occur over at least few monomer units to significantly increase hydrolysis susceptibility. In addition, we observe that sustaining tension across multiple monomer lengths by constraining molecular degrees of freedom further enhances hydrolysis susceptibility, leading to barrierless scission reactions for less substantial backbone deformations than otherwise. We then compute chain scission probabilities as functions of the backbone degrees of freedom, revealing complicated configurational inter-dependencies that impact the likelihood for hydrolytic degradation. The trends identified in our study suggest simple physical descriptions for the synergistic coupling between local mechanical deformation and environmental moisture in hydrolytic degradation of silicones.</div>

Anisotropic Hydrolysis Susceptibility in Deformed Polydimethylsiloxanes

<div>Chemical reactions involving the polydimethylsiloxane (PDMS) backbone can induce significant network rearrangements and ultimately degrade macro-scale mechanical properties of silicone components. Using two levels of quantum chemical theory, we identify a possible electronic driver for chemical susceptibility in strained PDMS chains and explore the complicated interplay between hydrolytic chain scissioning reactions, mechanical deformations of the backbone, water attack vector, and chain mobility. Density functional theory (DFT) calculations reveal that susceptibility to hydrolysis varies significantly with the vector for water attacks on silicon backbone atoms, which matches strain-induced anisotropic changes in the backbone electronic structure. Efficient semiempirical density functional tight binding (DFTB) calculations are shown to reproduce DFT predictions for select reaction pathways and facilitate more exhaustive explorations of configuration space. We show that concerted strains of the backbone must occur over at least few monomer units to significantly increase hydrolysis susceptibility. In addition, we observe that sustaining tension across multiple monomer lengths by constraining molecular degrees of freedom further enhances hydrolysis susceptibility, leading to barrierless scission reactions for less substantial backbone deformations than otherwise. We then compute chain scission probabilities as functions of the backbone degrees of freedom, revealing complicated configurational inter-dependencies that impact the likelihood for hydrolytic degradation. The trends identified in our study suggest simple physical descriptions for the synergistic coupling between local mechanical deformation and environmental moisture in hydrolytic degradation of silicones.</div>