Aug 2026· Journal of Membrane Biology· Vol 259· 0 citations· 40 references
Medicine
TL;DR
It is demonstrated that both peptides can be inserted into the preformed vesicles, and that the free energy difference between their partitioning is < 1 kcal/mol, disproving the hypothesis that KALP peptides are kinetically trapped and opening the doors for using this system for thermodynamic measurements to further test the additivity assumptions implicit in applications of hydrophobicity scales.
A lipid-shell modification to the protocol for assigning a residue’s character on a hydropathy (PARCH) scale is presented, in which the protein’s first hydration shell is enclosed by a lipid boundary layer during thermal annealing to establish a computationally affordable and physically meaningful approach to quantifying membrane hydropathy that is sensitive to residue identity, membrane depth, and cooperative hydration among tandem charged residues.
Ratnakshi Mandal, S. Nangia· Journal of Physical Chemistr...· 0 citations
The results reveal an unexpected dependence of partitioning energetics on both bilayer elastic energy and lipid packing defects, demonstrating how subtle changes in membrane physical properties could redirect protein folding pathways and thermodynamics.
Swadha Gupta, R. Mahalakshmi· Biochemistry· 0 citations
The model provides a computationally efficient framework for studying conformational ensembles and assembly of proteins at bilayer–water interfaces and is validated against Wimley–White free energies of transfer of hydrophobic peptides and against an experimentally refined conformational ensemble of a flexible membrane receptor.
Membrane pore stability is central to many processes involving membrane permeabilization, yet it remains unclear how the sequence of pore-localizing peptides can modify the energetics of the pore boundary. For large pores, the energetic cost associated with increasing pore size is described by the membrane line tension. Peptides capable of reducing line tension can therefore stabilize permeable membrane states, making their identification relevant for the design of membrane-active molecules. Here, we combine coarse-grained molecular dynamics simulations, free energy calculations, and evolutionary optimization algorithms to identify sequence features of α-helical peptides that reduce membrane line tension. The best-performing peptides consistently showed an amphipathic organization with aromatic-rich termini, a hydrophobic/aromatic membrane-facing nonpolar face, and a negatively charged polar face. These sequence features promoted peptide localization at the pore rim close to the intact bilayer and orientation parallel to the membrane edge. This binding geometry reorganized lipids at the pore rim and efficiently reduced the exposure of their hydrophobic tails to water, thereby reducing the energetic cost of the pore boundary. The main sequence and mechanistic trends identified in coarse-grained simulations were reproduced in all-atom simulations. Together, these results link peptide sequence to pore-rim localization, lipid reorganization, and ultimately line-tension reduction, providing molecular design principles for α-helical peptides that stabilize permeable membrane states.
Many transmembrane (TM) proteins contain an amphipathic helix. These amphipathic helices can sense lipid composition, stabilize membrane curvature, and mediate protein-protein interactions. Here, we combined solid-state NMR spectroscopy (ssNMR) and molecular dynamics simulations to characterize the structure and membrane interactions of a minimal TM and amphipathic construct (residues 101–146) from Mycobacterium tuberculosis (Mtb) FtsL. Amino-acid-specific 15N-labeled oriented-sample ssNMR spectra in POPC/POPG (4:1 molar ratio) membranes uniquely defined the orientation of the TM helix (residues 124–144), including a 16° tilt, but constrained only the amphipathic helix (residues 101–114) to a 90° tilt, leaving ambiguity in helical rotation and membrane burial depth. To resolve this ambiguity, we determined the two-dimensional free-energy surface using umbrella sampling simulations. The free-energy surface featured a major bound minimum, with the side chains of Leu104, Leu107, and Ile111 projecting into the hydrophobic core of the membrane and those of Arg103, Arg107, and Arg114 projecting sideways to interact with lipid headgroups. In pure POPC membranes, the bound basin contracted while the unbound basin expanded, as electrostatic attraction between Arg side chains and acidic POPG was replaced with repulsion by POPC’s choline group. The final structure of FtsL101–146 was refined by restrained molecular dynamics simulations in a POPC/POPG bilayer and further validated by 13C-13C correlation magic-angle-spinning NMR. Together, these results demonstrate that the amphipathic helix of FtsL functions as a membrane-interacting element that stabilizes the protein in the membrane environment and mediates the recruitment of downstream proteins to the divisome for Mtb cell division.
Jiaxing Fan, Ramesh Prasad, Rongfu Zhang et al.· Journal of the American Chem...· 0 citations
This study illustrates how subtle residue-localized conformational bias can affect the overall protein conformational dynamics influencing protein-protein interactions that are important for cellular functions and related to diseases.
Abir Ben Bouzayene, M. Sai, Alexis Jouin et al.· Angewandte Chemie· 0 citations
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