Walton-Raaby, M. | Search bioRxiv

bioRxiv2026

Computational Modeling of Functionalized Graphene Quantum Dots Binding to Tau Fibrils in Alzheimers Disease

The aggregation of Tau protein into straight filaments (SFs) and paired helical filaments (PHFs) is central to Alzheimers disease (AD) pathology and a key target for therapeutic inhibition. Graphene quantum dots (GQDs) are biocompatible nanomaterials that have shown promise in inhibiting amyloidogenic protein aggregation across related neurological pathologies. The effect of GQD functionalization on interactions with Tau aggregates (TAs) is poorly understood, though recent evidence suggests that anionic GQDs are effective TA inhibitors. In this study, we survey how GQD functionalization influences binding to SFs and PHFs to guide future development of therapeutic GQDs. We identify binding sites in SFs and PHFs, dock our GQD library to these sites, and perform molecular dynamics simulations on promising complexes, totaling 28 {micro}s of sampling. We discover that anionic GQDs preferentially bind to the positively charged SF large protofilament interface, whereas in PHFs, anionic GQDs have a modest binding preference for the C-shaped curve region. Binding of GQDs at the C-shaped curve in both TAs induces distinct protofilament conformational dynamics resembling a pinching motion to capture the GQD. Together, these binding modes may represent early intermediates of the TA disaggregation mechanism. We find that functional groups capable of possessing a negative charge (e.g., COO-, O-, and S-) produce impressive binding affinities. We propose that enriching these functionalizations during GQD synthesis and preparation, particularly sulfur as it is less studied, may yield more potent TA inhibitors and generalize to other amyloid pathologies with positively charged fibril cores. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/741532v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@d5d794org.highwire.dtl.DTLVardef@13c59e1org.highwire.dtl.DTLVardef@130c369org.highwire.dtl.DTLVardef@6d3385_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Surface electrostatic networks control hydrophobic core remodeling in a pH-dependent switching protein

Communication between protein surfaces and their buried cores is central to protein structure and function, yet this phenomenon remains challenging to predict and control at high resolution. Changes in the protonation of surface ionizable residues communicate with the hydrophobic core, for example, in diverse pH-dependent protein functions. Hisactophilin, a histidine-rich actin- and membrane-binding protein, provides a general model for exploring such communication as it exhibits a finely tuned pH-regulated myristoyl-switching function. Upon reversible proton binding, the myristoyl group shifts between being sequestered in the hydrophobic core and more solvent accessible. In the current study we utilize experimental and computational approaches we uncover how binding of [~]1.5 net protons alters electrostatic interactions involving ionizable residues distributed across much of the protein surface. These changes are transmitted to the hydrophobic core through dynamic communities of ionizable and hydrophobic residues which substantially rearrange upon switching. The effects of mutating individual ionizable residues are weaker than those of core hydrophobic residues, and only combined mutation of multiple ionizable residues caused substantial functional change. Together, these results reveal how communication between surface ionizable residues and the hydrophobic core is mediated by extensive interaction networks that reorganize in response to changes in protonation. These results may provide general insights for understanding protein cooperativity and the coupling of surface and core residues in protein function, disease, evolution, engineering, and design. Significance StatementHow changes on the protein surface, such as proton binding to ionizable amino acids, are communicated to the protein core to regulate protein stability and function remains ill-defined. Synthesis of experimental and computational analyses resolves the distributed networks of surface ionizable residue interactions coupled to the hydrophobic core that control pH-dependent myristoyl switching in hisactophilin. Small changes in protonation that create and alleviate local electrostatic repulsion give rise to protein-wide changes in fluctuating surface-core interactions. This distributed electrostatics-core coupling mechanism may help explain the often underrecognized and long-range impacts of ionizable residues in proteins and provide a framework for interpreting the effects of mutations in fundamental and applied protein science.

biophysics↗