Faculty Publications
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Item Molecular dynamics investigation of dipeptide - Transition metal salts in aqueous solutions(American Chemical Society service@acs.org, 2010) Santosh, M.S.; Lyubartsev, A.; Mirzoev, A.; Bhat, D.K.Molecular dynamics (MD) simulations of glycylglycine dipeptide with transition metal ions (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and Zn2+) in aqueous solutions have been carried out to get an insight into the solvation structure, intermolecular interactions, and salt effects in these systems. The solvation structure and hydrogen bonding were described in terms of radial distribution function (RDF) and spatial distribution function (SDF). The dynamical properties of the solvation structure were also analyzed in terms of diffusion and residence times. The simulation results show the presence of a well-defined first hydration shell around the dipeptide, with water molecules forming hydrogen bonds to the polar groups of the dipeptide. This shell is, however, affected by the strong electric field of divalent metal ions, which at higher ion concentrations lead to the shift in the dipeptide-water RDFs. Higher salt concentrations lead also to increased residence times and slower diffusion rates. In general, smaller ions (Cu2+, Zn2+) demonstrate stronger binding to dipeptide than the larger ones (Fe2+, Mn 2+). Simulations do not show any stronger association of peptide molecules indicating their dissolution in water. The above results may be of potential interest to future researchers on these molecular interactions. © 2010 American Chemical Society.Item Structural and dynamical properties of water in surfactant-like peptide-based nanotubes: Effect of pore size, tube length and charge(Elsevier B.V., 2021) Dilip, H.N.; Chakraborty, D.Atomistic molecular dynamics simulations were carried out to study the structural and dynamical properties of water molecules around pre-assembled surfactant-like peptide (SLP) nanotubes in aqueous media. These SLPs can be thought as a class of biocompatible and biodegradable surfactants for biomedical applications. Nanotube-like structures were considered where glycine and lysine (G6K) are taken as the constituents for the composition of the SLPs. The nanotubes considered were of different dimensions; such as 18 × 15 (number of peptides on the circumference x number of peptides layers), 18 × 12 and 16 × 12 for both charged and neutral analogues. The charged composition consists of protonated nitrogen in the lysine subunit and chlorine/bromine as counter ions. It is found that the neutral SLPs have less hydrated inner core consisting of more tetrahedral water compared to their charged analogues. The hydrogen bond lifetime of water-water and water-peptide molecules increases in the inner pore and found to be maximum for charged 16 × 12 system. Outside the pore, charged analogue of 18 × 15 have more water-water hydrogen bond lifetime compared to all other systems. However, protein-water hydrogen bond lifetime was found to be more for neutral analogues outside the pore due to more probable interactions of SLPs with water molecules. © 2020 Elsevier B.V.Item 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 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 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.Item Effect of peptide hydrophilicity on membrane curvature and permeation(American Institute of Physics, 2024) Mathath, A.V.; Chakraborty, D.Using a well-developed reaction coordinate in umbrella sampling, we studied the single peptide permeation through a model cancerous cell membrane, varying the hydrophilicity and the charge of the peptides. Two peptides, melittin and pHD108, were studied. The permeation mechanism differs from a barrel-stave-like mechanism to toroidal pore and vesicle formation based on the number and the placement of the hydrophilic amino acids in the peptide. Membrane curvature changes dynamically as the permeation process occurs. In the case of vesicles, the peptide traverses along a smooth, homogenous pathway, whereas a rugged, steep pathway was found when lipid molecules did not line up along the wall of the membrane (barrel-stave-like mechanism). A mechanism similar to a toroidal pore consists of multiple minima. Higher free energy was found for the permeating terminal containing charged amino acid residues. Vesicle formation was found for pHD108 peptide N-terminal with a maximum membrane thinning effect of 54.4% with free energy cost of 8.20 ± 0.10 kcal mol?1 and pore radius of 2.33 ± 0.07 nm. Insights gained from this study can help to build synthetic peptides for drug delivery. © 2024 Author(s).Item A new reaction coordinate to study the translocation pathway of cell-penetrating peptides across lipid bilayers: The cases of transportan-10 and penetratin(American Institute of Physics, 2025) Mathath, A.V.; Chakraborty, D.Translocation pathway of cell-penetrating peptides remains elusive, as it is hard to observe by experimental and theoretical studies, which limits their effective use. Furthermore, lipid dynamics influence the translocation pathway, which is often overlooked due to its slow timescale. Current studies lack the effect of multiple peptides on the translocation process. Therefore, in this work, we employ the umbrella sampling technique with a preferential lipid–peptide interaction term in the reaction coordinate to explore the translocation activity of penetratin and transportan-10 (TP10) peptides in a heterogeneous membrane. In experiments, they follow different pathways according to their concentration, but the cause of this difference is unknown. We considered single and multiple (two and four) peptide translocation processes to understand the differences. Self-aggregation process is taken into account for multiple peptides. The interaction between peptides and peptides–lipids is found to be important for a proper overview of the translocation process. Peptide translocation was found to be related to the dynamics of the lipids, which change during the translocation process, making the system complex to study. In the case of multiple penetratin translocation, the anionic lipids were found to aggregate on the positive curvature of the upper leaflet, helping fold the membrane. Lipid composition of the TP10 multiple peptide case was found random. The increased mass and size of the solute in this case helped attain a radius more than the threshold value, leading to pore formation. Free energy barriers of single TP10 and penetratin are found to be 45.4 ± 2 and 33.7 ± 0.8 kJ mol?1, respectively. © 2025 Author(s).