Jul 2026· Bio Systems· Vol 267, pp.
105885
· 0 citations· 41 references
Medicine
TL;DR
The framework is built as systems-level modeling that links hydration structure at atomic scale to macroscale, translating molecular recognition at the highest scales with information-like phase organization where continuity of water channels alone spontaneously emerges quantization and fractal-like phase conservation.
Abstract
We propose a theoretical and computational framework in which ordered hydration layers at biomolecular interfaces act as multi-scale coupled, phase-sensitive degrees of freedom that self-organize biological information processing at all scales. When biomolecular surfaces approach nanometer-to-subnanometer separations, overlapping hydration structures are represented by a shared-water coupling Hamiltonian incorporating evanescent and protonic channels. Coarse-graining yields a nonlocal complex-field description for locally connected hydration regions, while slow conformational variation introduces geometric-phase terms define vortex-like phase textures and routing-like correlation patterns. We further use a driven-dissipative Gross-Pitaevskii-type model as a phenomenological, not definitive, description of nonlinear hydration-sensitive collective modes. The model generates testable observables, including step-like phase responses, band-limited correlation windows, multi-timescale pump-probe relaxation, and sensitivity to temperature, osmolytes, and hydration state. We outline a GHz vector-network-analyzer and near-infrared pump-probe validation protocol on hydrated biomolecular films, together with negative controls for phase wrapping, RF leakage, standing waves, ionic conduction, and thermal drift. The framework is built as systems-level modeling that links hydration structure at atomic scale to macroscale, translating molecular recognition at the highest scales with information-like phase organization where continuity of water channels alone spontaneously emerges quantization and fractal-like phase conservation. Water as a singular unifying entity governing a bio-system has been neglected thus far.
Biomolecular condensates formed by liquid–liquid phase separation create dynamic, water-rich microenvironments that are essential for cellular organization, yet it is challenging to understand their internal aqueous phase. Here, we introduce Brønsted photoacids and photobases as a new class of environmental fluorescent probes to interrogate the water phase inside biomolecular condensates. Using in vitro condensates formed by intrinsically disordered poly lysine or poly arginine peptides with nucleotides, we combine steady-state and time-resolved fluorescence to resolve the probe’s excited-state proton transfer and subsequent proton recombination dynamics. We show that both photoacids and photobases remain largely solvated within poly lysine-based condensates, with only modest slowing of proton transfer relative to bulk water, consistent with a moderately more viscous aqueous environment. We mainly focus on photoacids, which exhibit strongly enhanced geminate proton recombination, attributed to nanometre-scale confinement of water within the condensates, inducing reflective boundaries for the dissociated proton. By modeling the recombination kinetics, we use the photoacid as a molecular ruler to estimate the dimensions of confined aqueous nanocavities, revealing characteristic maximum radii of ∼6 nm. Altering condensate composition systematically modulates these properties, with ATP- and poly arginine–based condensates displaying denser, less hydrated interiors. These findings establish excited-state proton transfer probes as powerful tools for quantifying nanoscale water confinement in biomolecular condensates, with implications for condensate function and molecular sequestration.
Biomolecular condensates represent unique microenvironments that organize intracellular biology and promote biochemical reactions. However, the biomolecular interactions driving condensate phase separation are often weak, transient, and heterogeneous. Investigating the structural biology and chemical properties of condensate interiors has therefore proven experimentally challenging, often requiring the use of perturbative probes. To overcome this challenge, we combine label-free optical scattering and vibrational spectroscopy approaches spanning ultraviolet, visible, mid-infrared, and terahertz wavelengths with deep-learning-based ensemble prediction of intrinsically disordered protein conformations. This suite of label-free approaches provides quantitative insights into protein-protein/protein-solvent interactions and the chemical properties of condensate interiors. Investigating the N-terminal domain of the RNA DEAD-box helicase 4 (DDX4), our experimental and computational results support a model of phase separation involving protein chain collapse, reduced dielectric, and water release. These molecular events are expected to enhance the strength of multivalent protein-protein interactions within condensates, creating a positive feedback loop important for condensate growth and phase separation.
Ethan A. Perets, Jacob A. Spies, Justin H. Cheong et al.· Biophysical Journal· 0 citations
Biomolecular condensates can undergo striking changes, such as transitioning from a liquid-like to a gel- or a solid-like aggregate due to changes in molecular interactions in response to changes in the biochemical environment. The question of how modified molecular interactions lead to such a transition in the material properties and spatial organization of condensates has not yet been elucidated. To address this question, we represent the biochemical environment as a triphasic mixture comprising a liquid-like protein-rich phase, a network-like protein-rich phase, and solvent. Owing to a change in the biochemical environment, protein molecules can reversibly switch between two conformational states. In a switched conformational state, the cross-linking domains of molecules are exposed which promote transient network formation in phase separated states. We develop a transient-network model and a continuum framework that couples phase separation, molecular switching, and dynamic cross-linking to predict condensate morphology and mechanics. The transient-network model predicts that a non-aging network behaves like a Maxwell fluid. When a network slowly ages via stabilization of cross-links, it shows Maxwell-like behavior and waiting time-dependent relaxation. However, a strongly aged network shows elastic recoil like characteristic of a Kelvin-Voigt solid. Our coupled continuum model demonstrates that the interplay of molecular switching and dynamic cross-linking in network formation shapes the spatial organization of condensate phases. In summary, this work demonstrates a mechanistic route explaining how conformational switching and molecular cross-linking regulate material properties and morphology of condensates.
Angstrom-scale confinement fundamentally controls the structure and dynamics of water, leading to behaviors that are very different from those observed in the bulk. Using many-body polarizable force fields combined with Grand Canonical Molecular Dynamics (GCMD) simulations, we investigate the behavior of water confined between multilayer graphene channels spanning 5.5 to 20 Å. We find that explicit modeling of the electronic polarization of graphene is essential: it suppresses the artificially solid-like ordering that arises with conventional nonpolarizable pairwise-additive descriptions based on Lennard-Jones interactions and restores liquid-like behavior even at the smallest channel spacings. The equilibrium densities obtained using GCMD simulations exhibit pronounced oscillations with channel spacing, reflecting discrete monolayer, bilayer, and trilayer packing regimes, which in turn give rise to strongly nonmonotonic variations in lateral diffusion. Structure factor analysis reveals that diffusion minima coincide with ordered, highly correlated configurations, whereas diffusion maxima arise from sparsely populated water configurations with lower density, where lateral correlations are also weaker. By integrating the hydration pressure, we construct the confinement-free-energy landscape and show that these oscillations emerge from a balance between energetic stabilization within compact layers and entropic penalties associated with restricted configurational freedom. As additional molecular layers form, confinement-induced structural, dynamical, and thermodynamic signatures progressively weaken and converge smoothly toward bulk-like behavior. Together, these results provide a unified microscopic picture of the behavior of water under extreme confinement, with direct implications for the design of ultrathin membranes, selective transport devices, and next-generation 2D nanofluidic platforms.
Alan Sam, Rahul Prasanna Misra, Shuang Luo et al.· ACS Nano· 0 citations
The distinct roles of Mg2+ and Ca2+ ions in biomolecular assembly can be understood through their different hydration dynamics, but a quantitative, causal link between the water-exchange kinetics of cations and assembly pathways has been lacking. Here, we establish this relationship using multi-force-field all-atom molecular dynamics simulations combined with enhanced sampling and Markov state model analysis. By systematically comparing force fields that inherently encode different hydration exchange rates, we show that the Mg2+ ion, with its kinetically inert hydration shell (microsecond water exchange), must undergo stepwise dehydration to coordinate aspartate residues. This kinetic barrier limits its ability to induce microphase separation on microsecond timescales, positioning the Mg2+ ion as a slow "structural reorganizer" that gradually disrupts preexisting Arg-Asp salt bridges. In contrast, the Ca2+ ion, with its rapidly exchanging hydration shell (picosecond-to-nanosecond water exchange), directly bridges multiple aspartate side-chains and acts as a fast "microphase separation trigger." Quantitative comparison of water-exchange rates across force fields, validated against experimental NMR data, establishes a causal chain from hydration kinetics to coordination modes to assembly timescales. Based on these results, we propose a "hydration clock" model in which the intrinsic water-exchange kinetics of cations dictates the fundamental timescales of biomolecular assembly. This work provides a kinetic framework, grounded in explicit-solvent molecular dynamics and multi-force-field validation, for understanding cation-specific effects and the rational design of time-programmable self-assembling systems.
Lei Bao, Benchao Zhu, Chenjie Feng et al.· Journal of Chemical Theory a...· 0 citations
A fundamental question in receptor-mediated endocytosis remains unanswered: what initial driving force brings ligands and receptors into close proximity? While previous models assume pre-existing contact and overlook this initiation problem, we propose that entropic forces from nanoscale biomolecules in crowded cellular environments provide the essential driving mechanism. We develop a unified continuum model rooted in the Onsager variational principle, where engulfment depth serves as the generalized coordinate and the driving force derives from a free energy landscape of entropic, binding, membrane, and cytoskeleton contributions. The framework naturally incorporates: (i) entropy-driven adhesion as initiation; (ii) ligand-receptor binding as the sustaining force; (iii) membrane deformation via the Helfrich-Canham Hamiltonian; and (iv) cytoskeleton viscoelasticity through the elastic-viscoelastic correspondence principle. The kinetic phase diagram predicts a critical biomolecule concentration for initiation, a lower bound of ligand density for complete engulfment, a finite size window for engulfable particles, and an optimal virus radius of 30--60 nm that decreases with increasing binding energy. The Onsager solubility condition naturally yields the phase boundaries. The model exhibits asymptotic consistency with the classic Asakura-Oosawa result in the large-particle flat-surface limit. Stiffer cells lead to longer engulfment times and narrower size windows. Strikingly, the optimal size matches HIV-1 dimensions under physiologically realistic parameters. This work provides a variational foundation for cellular uptake with implications for virology, nanotechnology, and drug delivery.