Mechanistic Insights into Adaptive Binding of Vitamins and Hormones at Hotspot-Enriched Interfaces of the Synaptotagmin 1 C2AB Domain
- 1University of Calcutta
Abstract
The present in silico study provided the adaptive binding of seven physiologically active molecules, including four non-peptide hormones (cortisol, estradiol, triiodothyronine, melatonin) and three vitamins (methyltetrahydrofolate, pyridoxal phosphate, thiamine), alongside argireline as a benchmark, at hotspot-enriched interfaces of full C2AB-domain of Synaptotagmin 1 (Syt1), using molecular docking study and molecular dynamics (MD) simulations. Linear correlations of MD-features and nonlinear KPCA-IG-based ranking of features and ligands yielded deeper mechanistic insights. All ligands exhibited spontaneous binding with strong negative {Delta}Gbinding values. Fifteen hotspots, clustered across the C2A, C2B, and C2AB-interlink regions, were dominated by hydrophobic and van der Waals interactions. Several hotspots and non-hotspots corresponded to Syt1 residues that are reported to link with Ca2+-dependent phenomena and membrane vesicular fusion. Solvent-excluded volume (VSE) analyses showed that local hotspot burial and global desolvation together influenced protein adaptability, distinguishing ligands with similar hotspots but divergent thermodynamics. Linear correlations established {Delta}Gbinding as an indicator of hydrophobic hotspot burial. KPCA-IG identified {Delta}VSE and RMSD as dominant mechanistic features capturing cooperative induced-fit responses. Pyridoxal phosphate, melatonin and triiodothyronine emerged as mechanistically top adaptive binders, involving adjustable desolvation, hotspot expansion, optimal flexibility and pose retention. Methyltetrahydrofolate and cortisol showed intermediate burial-dominated cooperativity. Argireline, thiamine and estradiol exhibited ligand-specific burial-dominated, pose-locked and adaptability-limited bindings. Overall, our study demonstrates that desolvation control, induced-fit adaptability and structural flexibility, not {Delta}Gbinding alone, govern Syt1-ligand binding, revealing Syt1 as a versatile presynaptic target for modulation by these bioactive molecules.
Related
- Learning Dynamic Neural Evidence Representations for Time-Adaptive Brain-Computer Interfaces
- GClnc1 as an emerging oncogenic regulator with mechanistic insights and clinical implications in human cancers
- Metabolite-centric Knowledge Graph Unveils Predictive and Mechanistic Insights through Self-supervised Multimodal Learning
- Mechanistic insights into proteolytic activation ofmembrane-bound NAC transcription factor SlNACMTF3 intomato plants under heat stress
- Mechanistic Insights into MYO1C-Mediated Rhodopsin Trafficking and Rod Photoreceptor Homeostasis.
BibTeX
@misc{hazra2026mechanistic,
title = {{Mechanistic Insights into Adaptive Binding of Vitamins and Hormones at Hotspot-Enriched Interfaces of the Synaptotagmin 1 C2AB Domain}},
author = {S. Hazra and B. K. Tiwary and A. Ghosh Chaudhuri and N. Chakrabarti},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.18.760018},
url = {https://www.biorxiv.org/content/10.64898/2026.10.18.760018v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Mechanistic Insights into Adaptive Binding of Vitamins and Hormones at Hotspot-Enriched Interfaces of the Synaptotagmin 1 C2AB Domain
AU - S. Hazra
AU - B. K. Tiwary
AU - A. Ghosh Chaudhuri
AU - N. Chakrabarti
PY - 2026
DA - 2026/10/18
PB - bioRxiv
DO - 10.64898/2026.10.18.760018
UR - https://www.biorxiv.org/content/10.64898/2026.10.18.760018v1
AB - The present in silico study provided the adaptive binding of seven physiologically active molecules, including four non-peptide hormones (cortisol, estradiol, triiodothyronine, melatonin) and three vitamins (methyltetrahydrofolate, pyridoxal phosphate, thiamine), alongside argireline as a benchmark, at hotspot-enriched interfaces of full C2AB-domain of Synaptotagmin 1 (Syt1), using molecular docking study and molecular dynamics (MD) simulations. Linear correlations of MD-features and nonlinear KPCA-IG-based ranking of features and ligands yielded deeper mechanistic insights. All ligands exhibited spontaneous binding with strong negative {Delta}Gbinding values. Fifteen hotspots, clustered across the C2A, C2B, and C2AB-interlink regions, were dominated by hydrophobic and van der Waals interactions. Several hotspots and non-hotspots corresponded to Syt1 residues that are reported to link with Ca2+-dependent phenomena and membrane vesicular fusion. Solvent-excluded volume (VSE) analyses showed that local hotspot burial and global desolvation together influenced protein adaptability, distinguishing ligands with similar hotspots but divergent thermodynamics. Linear correlations established {Delta}Gbinding as an indicator of hydrophobic hotspot burial. KPCA-IG identified {Delta}VSE and RMSD as dominant mechanistic features capturing cooperative induced-fit responses. Pyridoxal phosphate, melatonin and triiodothyronine emerged as mechanistically top adaptive binders, involving adjustable desolvation, hotspot expansion, optimal flexibility and pose retention. Methyltetrahydrofolate and cortisol showed intermediate burial-dominated cooperativity. Argireline, thiamine and estradiol exhibited ligand-specific burial-dominated, pose-locked and adaptability-limited bindings. Overall, our study demonstrates that desolvation control, induced-fit adaptability and structural flexibility, not {Delta}Gbinding alone, govern Syt1-ligand binding, revealing Syt1 as a versatile presynaptic target for modulation by these bioactive molecules.
ER -