Faculty Publications

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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.
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.
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.
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.

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