Faculty Publications
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Item Designing Reaction Coordinate for Ion-Induced Pore-Assisted Mechanism of Halide Ions Permeation through Lipid Bilayer by Umbrella Sampling(American Chemical Society, 2023) Mathath, A.V.; Das, B.K.; Chakraborty, D.Ion permeation mechanism through lipid membranes helps to understand cellular processes. We propose new reaction coordinates that allow ions to permeate according to their water affinity and interaction with the hydrophilic layer. Simulations were done for three different halides (F-, Cl-, and I-) in two different lipid bilayers, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dinervonoyl-sn-glycero-3-phosphocholine (DNPC). It is found that the involvement of the water molecules decreases the free energy barrier. The ions were found to follow different pathways for permeation. Formation of proper pores required a collaboration effort of the hydration shell water molecules and the hydrophilic lipid layer, which was favored in the case of Cl- ions. The optimum charge density and good water affinity of Cl- with respect to F- and I- ions helped to form the pore. The effect was prominently seen in the case of DNPC membrane because of its higher hydrophobic thickness. The umbrella sampling results were compared with other methods such as the Markov state model (MSM) and well-tempered metadynamics (WT-metaD). © 2023 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).