Identification of Transient Allosteric Cryptic Pockets in Human HMGB1 (PDB: 2YRQ) via High-Throughput Multiverse Conformational Sampling
Year: 2026
Type: preprint
Abstract: Human High Mobility Group Box 1 (HMGB1, PDB: 2YRQ) is a critical proinflammatory cytokine and a pivotal downstream therapeutic target in neurodegenerative disorders, particularly within the circPTK2-HMGB1 regulatory axis in Parkinson's disease (PD). Despite its pathological significance, HMGB1 is conventionally considered "undruggable" due to the lack of static, deep active binding sites in its crystal/NMR structures. In this work, we employ the LSI Tool™, a novel high-throughput conformational sampling platform integrated with patented hardware-aware GPU acceleration algorithms, to explore the dynamic conformational ensemble of HMGB1 under physiological thermal fluctuations (310.15 K). Operating at an extraordinary sampling throughput exceeding 399,000+ Frames Per Second (FPS, where 1 FPS = 1 fs physical time propagation) on a single mid-range consumer-grade GPU, the engine achieved multi-nanosecond trajectory exploration across parallel Multiverse execution branches. Our dynamic ensemble analysis identified three highly converged, transient allosteric "cryptic pockets" (Sites A, B, and C) located at the tandem HMG-box domain interfaces. Spatial clustering revealed sub-Angstrom Euclidean centroid convergence (Δd < 0.2 Å) across independent Multiverse sampling runs. These transient pockets represent high-value druggable envelopes for small-molecule allosteric modulators aimed at blocking extracellular HMGB1-TLR4/RAGE signaling. This pre-print serves as a formal priority disclosure for the spatial coordinates, gating residues, and dynamic conformational snapshots of HMGB1 for targeted lead discovery.
Author: Chen, Tung-Hsiang
Institution: Taipei Medical University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7171529917
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