Faculty Publications
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Item Temperature-Dependent Conformational Evolution of SARS CoV-2 RNA Genome Using Network Analysis(American Chemical Society, 2021) Singh, O.; Venugopal, P.P.; Mathur, A.; Chakraborty, D.Understanding the dynamics of the SARS CoV-2 RNA genome and its dependence on temperature is necessary to fight the current COVID-19 crisis. Computationally, the handling of large data is a major challenge in the elucidation of the structures of RNA. This work presents network analysis as an important tool to see the conformational evolution and the most dominant structures of the RNA genome at six different temperatures. It effectively distinguished different communities of RNA having structural variation. It is found that at higher temperatures (348 K and above), 80% of the RNA structure is destroyed in both the SPC/E and mTIP3P water models. The thermal denaturation free energy change ??Gvalue calculated for the long-lived structure at higher temperatures of 348 and 363 K ranges from 2.58 to 2.78 kcal/mol for the SPC/E water model, which agrees well with the experimentally reported thermal denaturation free energy range of 2.874 kcal/mol of SARS CoV-NP at normal pH. At higher temperatures, the stability of RNA conformation is found to be due to the existence of non-native base pairs in the SPC/E water model. © 2021 American Chemical SocietyItem Preferential binding affinity of ions and their effect on structure and dynamics of water near antimicrobial peptide(Elsevier B.V., 2021) Singh, O.; Chakraborty, D.Water containing dissolved salts is often found to play important roles in many chemical and biological processes. They affect the stability of the amino acids and proteins by altering the liquid water structure. The formation of a mixture of non-uniform density regions in liquid water; commonly known as Low-density water and High-density water is a well-known fact experimentally; which lends uniqueness to the ubiquitous water. The behavior of these different types of water at the interface and the bulk region of the biomolecules around the hydrophobic and hydrophilic residues under the influence of different alkali metal ions, such as LiCl, NaCl, and KCl is an important unexplored question in understanding of many biomolecular processes. To address this, we carried out MD simulation of antimicrobial peptide (PDB ID: 5Z32) for two different model potentials (CHARMM-SPC/E and AMBER-TIP4P) and performed the structural analysis of water in terms of the radial distribution function, number of hydrogen bonds, orientation, tetrahedral order parameter, voids analysis to analyze the related dynamical properties like preferential binding affinity, diffusion, hydrogen bond dynamics, entropy. The water molecules around the hydrophilic environment are found to be more disruptive containing more broken hydrogen bonds in comparison to the hydrophobic environment. It is also found that the water molecules present near the protein surface are of low density and that near the bulk is of high density. This leads to the higher self-diffusion coefficient of the water molecules and less hydrogen bond lifetime at the bulk. The maximum difference is found for the solutions containing high charge density, Lithium ions. Lithium ions have a strong preferential binding affinity towards protein surface resulting in strong solvation shells containing more tetrahedral-like water structure which has low diffusion, low entropy, and higher hydrogen bond lifetime. The diffusion of the water molecules, however, increases towards the higher solvation shells. Potassium on the other hand has less preference to live on protein surfaces resulting in similar diffusion values in the bulk and interface water molecules. © 2021 Elsevier B.V.Item Influence of Ion Specificity and Concentration on the Conformational Transition of Intrinsically Disordered Sheep Prion Peptide(John Wiley and Sons Inc, 2022) Singh, O.; Kumar das, B.; Chakraborty, D.The structural sensitivity of the intrinsically disordered proteins with the ions has been observed experimentally; however, it is still unclear how the presence of different metal ions affects structural stability. We performed an atomistic molecular dynamics simulation of sheep prion peptide (142–167) in presence of different monovalent, divalent ions at various concentrations to find out the effect of the size, charge, and ionic concentration on the structure of the peptide. It is found that Li+ ions have a higher survival probability compared to Na+, K+, and Mg2+ affecting the solvation structure of the protein leading to the alpha-helix structure. At high concentration, due to the increase in the ion-solvent and counter-ion interactions, the effect of the ions is screened on the surface of the protein and hence no ion specificity is observed. This study demonstrates how ions can be used to regulate the protein structure and function that can help in designing drugs. © 2022 Wiley-VCH GmbH.Item Understanding the role of water on temperature-dependent structural modifications of SARS CoV-2 main protease binding sites(Elsevier B.V., 2022) Venugopal, P.P.; Singh, O.; Chakraborty, D.Thermally stable and labile proteases are found in microorganisms. Protease mediates the cleavage of polyproteins in the virus replication and transcription process. 6 µs MD simulations were performed for monomer/dimer SARS CoV-2 main protease system in both SPC/E and mTIP3P water model to analyse the temperature-dependent behaviour of the protein. It is found that maximum conformational changes are observed at 348 K which is near the melting temperature. Network distribution of evolved conformations shows an increase in the number of communities with the rise in the temperature. The global conformation of the protein was found to be intact whereas a local conformational space evolved due to thermal fluctuations. The global conformational change in the free energy ΔΔG value for the monomer and the dimer between 278 K and 383 K is found to be 2.51 and 2.10 kJ/mol respectively. A detailed analysis was carried out on the effect of water on the temperature-dependent structural modifications of four binding pockets of SARS CoV-2 main protease namely, catalytic dyad, substrate-binding site, dimerization site and allosteric site. It is found that the water structure around the binding sites is altered with temperature. The water around the dimer sites is more ordered than the monomer sites regardless of the rise in temperature due to structural rigidity. The energy expense of binding the small molecules at substrate binding is less compared to the allosteric site. The water-water hydrogen bond lifetime is found to be more near the cavity of His41. Also, it is observed that mTIP3P water molecules have a similar effect to that of SPC/E water molecules on the main protease. © 2022 Elsevier B.V.Item Exploring the multiple conformational states of RNA genome through interhelical dynamics and network analysis(Elsevier Inc., 2022) Singh, O.; Venugopal, P.P.; Mathur, A.; Chakraborty, D.The structural variation of RNA is often very transient and can be easily missed in experiments. Molecular dynamics simulation studies along with network analysis can be an effective tool to identify prominent conformations of such dynamic biomolecular systems. Here we describe a method to effectively sample different RNA conformations at six different temperatures based on the changes in the interhelical orientations. This method gives the information about prominent states of the RNA as well as the probability of the existence of different conformations and their interconnections during the process of evolution. In the case of the SARS-CoV-2 genome, the change of prominent structures was found to be faster at 333 K as compared to higher temperatures due to the formation of the non-native base pairs. ΔΔG calculated between 288 K and 363 K are found to be 10.31 kcal/mol (88 nt) considering the contribution from the multiple states of the RNA which agrees well with the experimentally reported denaturation energy for E. coli α mRNA pseudoknot (∼16 kcal/mol, 112 nt) determined by calorimetry/UV hyperchromicity and human telomerase RNA telomerase (4.5–6.6 kcal/mol, 54 nt) determined by FRET analysis. © 2022 Elsevier Inc.Item Growth Reaction of Gold Nanorods in the Presence of Mutated Peptides and Amine-Modified Single-Stranded Nucleic Acids(John Wiley and Sons Ltd, 2023) Sahu, J.K.; Singh, O.; Chakraborty, D.; Sadhu, K.K.Conformation of biomolecules like DNA, peptides and amino acids play vital role during nanoparticle growth. Herein, we have experimentally explored the effect of different noncovalent interaction between a 5′-amine modified DNA sequence (NH2−C6H12-5′-ACATCAGT-3′, PMR) and arginine during the seed-mediated growth reaction of gold nanorods (GNRs). Amino acid-mediated growth reaction of GNRs results in a snowflake-like gold nanoarchitecture. However, in case of Arg, prior incubation of GNRs with PMR selectively produces sea urchin-like gold suprastructures, via strong hydrogen bonding and cation-π interaction between PMR and Arg. This distinctive structure formation strategy has been extended to study the structural modulation caused by two structurally close α-helical RRR (Ac-(AAAAR)3A−NH2) peptide and the lysine mutated KKR (Ac−AAAAKAAAAKAAAARA−NH2) peptide with partial helix at the amino terminus. Simulation studies confirm that a greater number of hydrogen bonding and cation-π interaction between the Arg residues and PMR resulted in the gold sea urchin structure for RRR peptide against KKR peptide. © 2023 Wiley-VCH GmbH.Item Exploring the Barriers in the Aggregation of a Hexadecameric Human Prion Peptide through the Markov State Model(American Chemical Society, 2023) Das, B.K.; Singh, O.; Chakraborty, D.The prefibrillar aggregation kinetics of prion peptides are still an enigma. In this perspective, we employ atomistic molecular dynamics (MD) simulations of the shortest human prion peptide (HPP) (127GYMLGS132) at various temperatures and peptide concentrations and apply the Markov state model to determine the various intermediates and lag phases. Our results reveal that the natural mechanism of prion peptide self-assembly in the aqueous phase is impeded by two significant kinetic barriers with oligomer sizes of 6-9 and 12-13 peptides, respectively. The first one is the aggregation of unstructured lower-order oligomers, and the second is fibril nucleation, which impedes the further growth of prion aggregates. Among these two activation barriers, the second one is found to be dominant irrespective of the increase in temperature and peptide concentration. These lag phases are captured in all three different force-field parameters, namely, GROMOS-54a7, AMBER-99SB-ILDN, and CHARMMS 36m, at different concentrations. The GROMOS-54a7 and AMBER-99SB-ILDN force fields showed a comparatively higher percentage of β-sheet formation in the metastable aggregate that evolved during the aggregation process. In contrast, the CHARMM-36m force field showed mostly coil or turn conformations. The addition of a novel catecholamine derivative (naphthoquinone dopamine (NQDA)) arrests the aggregation process between the lag phases by increasing the activation barrier for the Lag1 and Lag2 phases in all of the force fields, which further validates the existence of these lag phases. The preferential binding of NQDA with the peptides increases the hydration of peptides and eventually disrupts the organized morphology of prefibrillar aggregates. It reduces the dimer dissociation energy by −24.34 kJ/mol. © 2023 American Chemical Society.Item Effect of Water Models on The Stability of RNA: Role of Counter-Ions(Elsevier B.V., 2023) Singh, O.; Venugopal, P.P.; Chakraborty, D.Various force fields and water model potentials influence significantly RNA conformations. The polyanionic nature of RNA attracts the water molecules and the counter ions which in turn affects their stability. The interfacial water's structural and dynamic aspects affect the RNA's base-pair opening and denaturation by breaking or making inter/intra-hydrogen bonds. Herein, we employed an MD simulations study using SPC/E and modified TIP3P water models in combination with different force fields CHARMM and AMBER to find their influence on the hydration shell of the SARS-CoV-2 RNA genome at different temperatures. AMBER-mTIP3P model was found to give more dynamic and transient conformations for RNA. The lower dielectric constant of the SPC/E model helps in the formation of the ion-contact pair near the negatively charged phosphate group (Na+-PO4−) leading to strong RNA-ion interaction and strong hydration shells having higher hydrogen bond lifetime. The Na+ ion survival probability at the interface was found to be more in the SPC/E model. At lower temperatures, the water molecules inside these hydration shells were found to be inhomogeneous, with lower void space, higher-coordinated, and non-tetrahedral. The higher dielectric constant of the mTIP3P model screened out the attraction between the ion pairs leading to a more homogenous solvation shell having a lesser hydrogen bond lifetime and more diffusive water. The distribution of the ions near the RNA structure is confirmed by metadynamics simulations. Both water models were found to disrupt the base pair orientation due to the formation of water bridges between the O2ʹ group of RNA and the water molecules. © 2023 The Author(s)Item Study of Correlated Motions to Detect the Conformational Transitions of the Intrinsically Disordered Sheep Prion Peptide(American Chemical Society, 2024) Chakraborty, D.; Singh, O.; Parameswaran, D.Intrinsically disordered proteins (IDPs) are known for their random structural changes throughout their sequence based on the environment. The mechanism underlying these structural changes is difficult to explain. All biological processes are known to follow the direction through which they act. A study of the correlated motion can help to understand the direction of the change. Herein, we introduced the multivariate statistical analysis (MSA) technique to study the correlated motion of the peptide. The correlated motion of the sheep prion peptide was studied with the change in the temperature and solvent. These techniques helped to identify the contributing residual motions that helped to form the different secondary structures of the protein and also the triggering factors that drive these sorts of residual motions. The structural details match the experimentally reported data. It was found that the direction of the change of the secondary structure for this peptide shifted from the C-terminal to the N-terminal with an increase in the temperature. It was found that the involvement of the hydrophobic residues present at the C-terminal and the middle residues (residues 12-17) is responsible for forming a β-sheet at the normal temperature. Hydration water was found to play an important role in this change. Insights gained from this study can be used to design strategies for desirable structural changes in the IDPs. © 2024 American Chemical Society.