Aug 2026· Journal of Physical Chemistry B· Vol 130, pp. 8616 - 8623· 0 citations· 22 references
Medicine
TL;DR
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.
Abstract
Understanding how amino acid residues partition from water into lipid bilayers is fundamental to membrane protein folding, stability, and function. Existing hydrophobicity scales derive from isolated protein systems, organic solvent approximations, or computationally expensive free energy methods, each with significant limitations in capturing the full thermodynamic and topographic complexity of membrane protein environments. Here we present a lipid-shell modification to the protocol for assigning a residue’s character on a hydropathy (PARCH) scale, in which the protein’s first hydration shell is enclosed by a lipid boundary layer during thermal annealing. This modification preserves the core PARCH methodologyevaluating water retention around residues as a function of temperaturewhile imposing the chemical potential boundary condition appropriate for membrane-embedded proteins. Using the OmpLA host–guest system, we compute PARCH values (PVs) that align with the experimental water-to-bilayer transfer free energy scale of Moon and Fleming (PNAS, 108, 10174–10177, 2011) without calibration to that data. We further demonstrate that depth-dependent PV profiles for arginine and leucine mirror experimentally measured partition energies across six membrane positions. Finally, PVs for a tandem arginine double mutant reveal a per-residue cooperative hydration redistribution that provides microscopic insight into thermodynamic cooperativity previously measured experimentally. Together, these results establish the lipid-shell PARCH modification as 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.
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.
Protein stabilizers and denaturants can be used to elucidate the fundamental principles of hydration, which is crucial for biological functions and biotechnology. Despite decades of work, existing molecular models of such stabilizers and denaturants have not yet been fully validated because few experimental methods can detect water structures within the hydration shell in situ under ambient conditions. Here, we devise a molecular model guided by the application of chiral-selective vibrational sum frequency generation spectroscopy to a solvated protein. We show that urea disrupts the first hydration shell, weakening the protein’s hydrogen bonds. Conversely, trimethylamine N-oxide resides outside the shell and stabilizes the protein by strengthening water hydrogen bonds within the first hydration shell. In mixtures, trimethylamine N-oxide drives urea out of the shell, neutralizing urea’s destabilizing effect. We conclude that protein stability directly correlates with first hydration shell integrity. These insights have broad implications for understanding solvent effects on biocatalysis and heterogeneous cellular environments.
Zhi-Jie Wang, Matthew Tremblay, Nicholas Hatzis-Schoch et al.· Journal of the American Chem...· 0 citations
Membrane curvature plays a central role in a wide range of biological processes, yet a quantitative and transferable description of its underlying energetics remains challenging. In this work, we develop a "reaction coordinate" within the Umbrella-Sampling framework to compute the free-energy cost associated with local membrane bending in both coarse-grained and atomistic simulations. The methodology is systematically validated across diverse lipid environments, including pure bilayers with varying tail unsaturation, tail length, and headgroup chemistry, where it reproduces established trends in membrane-mechanical rigidity. Extension to mixed lipid systems further captures composition-dependent modulation of bending energetics, including cholesterol-induced responses. Finally, we apply the framework to membrane-active proteins with distinct curvature-generation mechanisms and demonstrate that the method successfully captures the protein modulation of the free-energy cost of local membrane deformation. Furthermore, the method is transferable to atomistic membrane systems while maintaining reasonable computational efficiency, providing a unified approach for quantifying membrane bending energetics across lipids, proteins, and simulation scales.
Rupam Dey, Jatin Soni, Taraknath Mandal· Journal of Chemical Theory a...· 0 citations
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. Kyrychenko, A. Ladokhin· Journal of Membrane Biology· 0 citations
Hydrophobic hydration underpins processes central to chemistry, biology, and technology, from protein folding and molecular self-assembly to catalysis and nanomaterial dispersion. However, direct structural information on water surrounding large hydrophobic molecules remains scarce due to their very low solubility. Here, we overcome this limitation by using low-temperature vapor codeposition to form amorphous mixtures of water and anthracene, a hydrophobic “mini-graphene”. We then resolve the structure of anthracene’s first hydration shell by neutron diffraction. The linear polycyclic aromatic hydrocarbon induces distinct structural motifs in its hydration shell. Water molecules above and below the outer aromatic rings exhibit one broken water–water hydrogen bond enabling weak O–H···π interactions with the solute, while a pronounced “dewetting” effect emerges at the central ring. These findings provide experimentally constrained structural insights into the hydration around a large hydrophobe under conditions where conventional liquid-state experiments are not feasible.
Gustavo Madrigal, Christos Vasilopanagos, T. Headen et al.· Journal of Physical Chemistr...· 0 citations
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