Genetics of Parkinson's disease

Allostery is an intrinsic property of many globular proteins and enzymes that is indispensable for cellular regulatory and feedback mechanisms. Recent theoretical and empirical observations indicate that allostery is also manifest in intrinsically disordered proteins, which account for a substantial proportion of the proteome. Many intrinsically disordered proteins are promiscuous binders that interact with multiple partners and frequently function as molecular hubs in protein interaction networks. The adenovirus early region 1A (E1A) oncoprotein is a prime example of a molecular hub intrinsically disordered protein. E1A can induce marked epigenetic reprogramming of the cell within hours after infection, through interactions with a diverse set of partners that include key host regulators such as the general transcriptional coactivator CREB binding protein (CBP), its paralogue p300, and the retinoblastoma protein (pRb; also called RB1). Little is known about the allosteric effects at play in E1A–CBP–pRb interactions, or more generally in hub intrinsically disordered protein interaction networks. Here we used single-molecule fluorescence resonance energy transfer (smFRET) to study coupled binding and folding processes in the ternary E1A system. The low concentrations used in these high-sensitivity experiments proved to be essential for these studies, which are challenging owing to a combination of E1A aggregation propensity and high-affinity binding interactions. Our data revealed that E1A–CBP–pRb interactions have either positive or negative cooperativity, depending on the available E1A interaction sites. This striking cooperativity switch enables fine-tuning of the thermodynamic accessibility of the ternary versus binary E1A complexes, and may permit a context-specific tuning of associated downstream signalling outputs. Such a modulation of allosteric interactions is probably a common mechanism in molecular hub intrinsically disordered protein function.

Modulation of Allostery by protein intrinsic Disorder

[Biochemistry of Parkinson's disease].

Recent advances in design of new urease inhibitors: A review.

Ureases: Historical aspects, catalytic, and non-catalytic properties - A review.

Recently, small compounds from Indian spices (Carnosol, Arjunglucoside-I, and Rosmanol) have been identified as SARS-CoV-2 main protease (Mpro) inhibitors. The structural dynamics and characteristic features of binding of these small molecules to the SARS-CoV-2 Mpro are not well understood. Here, we have constructed the potential of mean force (PMF) for dissociating Mpro-small molecule inhibitor complexes from the umbrella sampling simulations using the weighted histogram analysis method. Mpro-small molecule inhibitor complexes exhibited relatively higher dissociation energy values than the alpha-ketoamide-Mpro complex (positive control) from the PMF calculations. We found that binding affinity between protein and ligand is higher in Mpro-Arjunglucoside-I complex [∆Gbind = -19.74 kcal mol-1 from MM-GBSA and ∆Gbind = -9.13 kcal mol-1 from MM-PBSA] than in other three SARS-CoV-2 small molecule complexes. The MM-GBSA/MM-PBSA calculations revealed that the small molecule inhibitors studied in this work have substantially higher binding affinity for Mpro. We found the residues present in SARS-CoV-2 Mpro's binding pocket contributed the most binding free energy to SARS-CoV-2 Mpro-small molecule interactions. Our findings emphasize the structural and binding features of the identified small molecule inhibitors with SARS-CoV-2 Mpro, which could be relevant in developing therapeutic candidates to combat SARS-CoV-2.

Computational Investigation on the Efficiency of Small Molecule Inhibitors Identified from Indian Spices against SARS-CoV-2 Mpro

The COVID-19 pandemic started at the onset of 2020 and still thriving due to its continuous mutation and evolution into new strains. Omicron strain has been recently categorized as a variant of concern(VoC) by WHO and based on mutations, it is divided into BA.1 and BA.2. In this study, we compared the interaction profile of RBD of the spike protein of the BA.1 and BA.2 variant of SARS-CoV-2 with ACE2 receptor. From the molecular dynamics simulation study, we observed the spike protein of BA.1, and BA.2 variant utilizes unique strategies to have a stable binding with ACE2. The binding affinity of the spike protein of the BA.2 variant-ACE2 complex is indeed high (GBTOT=-23.87 kcal/mol) in comparison with the spike protein of BA.1 variant-ACE2 complex (GBTOT=5.38 kcal/mol). Stable binding of spike protein to ACE2 is essential for virus entry, and the interactions between them should be understood well for the treatment modalities.

/pdf/impact-of-mutations-in-the-sars-cov-2-spike-rbd-region-of-ba-2kpp1dh0.pdf

Impact of Mutations in the SARS-CoV-2 Spike RBD Region of BA.1 and BA.2 Variants on its Interaction with ACE2 Receptor Protein



Resveratrol (RSV), a polyphenolic compound, is reported to have anti-aggregation properties against Amyloid-beta peptides. It is, therefore, significant to understand the mechanism of inhibition of Aβ1-42 peptide aggregation by the RSV at the molecular level. We have used Molecular docking along with Molecular dynamics (MD) simulation techniques to address the role of RSV in the inhibition of Aβ1-42 pep-tide aggregation.



To understand the role of Resveratrol on the Aβ1-42 peptide aggregation.



In this computational study, we have docked the RSV to Aβ1-42 peptide using Molecular Docking software and then performed MD simulation for the Aβ1-42 peptide monomer Aβ1-42 peptide-RSV complex using the AMBER force field. From the analysis of MD trajectories, we obtained salient structural features and determined the Binding Free Energy(BFE) and Per-residue Energy Decomposition Analysis (PRED) using MM-PBSA/GBSA method.



The secondary structure and the conformational analysis obtained from MD trajectories show that the binding of RSV with the Aβ1-42 peptide monomer causes an increase in the helical content in the structure of the Aβ1-42 peptide. The BFE and PRED results show a high binding affinity (GBtotal=-11.07 kcal mol-1; PBtotal= -1.82 kcal mol-1) of RSV with Aβ1-42 peptide. Also, we found the RSV to interact with cru-cial residues (Asp 23 and Lys 28) of the Aβ1-42 peptide. These residues play a signif-icant role in facilitating the formation of toxic amyloid oligomers and amyloid fibrils. The salt bridge interaction between these residues D23–K28 was found to be destabi-lized in the Aβ1-42 peptide when it is complexed with RSV.



In summary, it can be concluded that Resveratrol greatly aids the preven-tion of Aβ1-42 peptide aggregation. Therefore, it can be considered a possible drug candidate for therapeutic strategies for Alzheimer’s disease.


Insights Into Resveratrol as an Inhibitor Against Aβ1-42 Peptide Aggregation: A Molecu-lar Dynamics Simulation Study

Killer Ig like receptor (KIR) and the human leukocyte antigen (HLA) complex shows extensive polymorphism which has significance in context of disease association and evolution of immune responses. We have examined here the allelic diversity and copy number variation (CNV) of KIR2DL1 binding affinity with its cognate ligand HLA-C and its association with Head and Neck Squamous Cell Carcinoma (HNSCC) in a hospital based case-control study with 204 HNSCC patients and 225 non cancer participants in populations of Assam, North-East India. KIR2DL1*003 was seen at highest frequency of 79.1%. HLA-C*04 and HLA-C*07 were the most frequent HLA-C allotypes (28.5% and 25% respectively). The combined genotype of KIR2DL1*003-HLA-C2 was positively associated with HNSCC ( p = 0.0152; OR = 1.9, 95%CI 1.118–2.534) and was more frequent in younger age group patients suggesting positive association with early onset of disease ( p = 0.0008 OR = 2.0, 95% CI 1.157–2.363). HNSCC patients with KIR2DL1*003-HLA-C2 genotype had higher CNV of KIR2DL1 gene hinting at higher NK activation threshold which was supported by affinity binding of KIR2DL1 alleles with HLA-CW4 and by higher SHP2 phosphatase activity. Positive association of CNV with tumor proliferation, angiogenesis, cancer relapse and advance tumor stage suggested compromise of NK activation for anti-tumor response, consistent with downregulated cytokine response. In conclusion, our data suggested that higher affinity binding alleles together with higher CNV of inhibitory KIR2DL1 compromised immune surveillance in HNSCC and opens up the possibility of the use of KIR-HLA allotyping as prognostic markers. 

Higher affinity binding alleles and copy number variation of inhibitory KIR2DL1 gene influence the immune surveillance in head and neck squamous cell carcinoma in the population of Assam, North-East India

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has undergone multiple significant mutations since its detection in 2019 in Wuhan, China. The emergence of new SARS-CoV-2 variants that can spread rapidly and undermine vaccine-induced immunity threatens the end of the COVID-19 pandemic. The delta variant (B.1.617.2) that emerged in India challenges efforts to control the COVID-19 pandemic. In addition to Delta, so-called Delta Plus sub-variants (B.1.617.2.1 and B.1.617.2.2) have become a new cause of global concern. Here we compare the interaction profile of RBD of the spike protein of the Delta and Delta-Plus variant of SARS-CoV-2 with the ACE2 receptor. From the molecular dynamics simulation, we observed the spike protein of Delta and Delta-Plus variant of SARS-CoV-2 utilizes unique strategies to have stable binding with ACE2. Using MM-GBSA/MM-PBSA algorithms, we found the binding affinity of spike protein of the Delta- variant-ACE2 complex is indeed high (GBTOT = -39.36 kcal mol-1, PBTOT= -17.52 kcal mol-1) in comparison with spike protein of Delta-Plus variant-ACE2 Complex (GBTOT = -36.83 kcal mol-1, PBTOT = -16.03 kcal mol-1). Stable binding of spike protein to ACE2 is essential for virus entry, and the interactions between them should be understood well for the treatment modalities.

/pdf/effect-of-mutations-in-the-sars-cov-2-spike-rbd-region-of-2qocapaa.pdf

Venkata Satish Kumar Mattaparthi

Papers

Computational Investigation on the Efficiency of Small Molecule Inhibitors Identified from Indian Spices against SARS-CoV-2 Mpro

Impact of Mutations in the SARS-CoV-2 Spike RBD Region of BA.1 and BA.2 Variants on its Interaction with ACE2 Receptor Protein

Insights Into Resveratrol as an Inhibitor Against Aβ1-42 Peptide Aggregation: A Molecu-lar Dynamics Simulation Study

Higher affinity binding alleles and copy number variation of inhibitory KIR2DL1 gene influence the immune surveillance in head and neck squamous cell carcinoma in the population of Assam, North-East India

Effect of Mutations in the SARS-CoV-2 Spike RBD Region of Delta and Delta-Plus Variants on its Interaction with ACE2 Receptor Protein