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Daily Signal March 04, 2026 · 8 min read

Issue #60: Anomalous Effect of Denaturant on Protein Unfolding Dynamics Revealed by Single Molecule Manipulation Experiments.

Protein Design Digest - 2026-03-04 - Investigation of the potential mechanism by which methylparaben induces psoriasis: an integrated study using network toxicology, molecular docking, molecular dynamics simulation, and eight machine learning algorithms.

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Signal of the Day

Anomalous Effect of Denaturant on Protein Unfolding Dynamics Revealed by Single Molecule Manipulation Experiments.

High temperatures and chemical denaturants in bulk experiments, as well as mechanical forces in single-molecule studies, typically promote protein unfolding. In this study, we report an unexpected decrease in the unfolding rate of cold shock protein (Csp) at low concentrations of guanidine hydrochloride (GuHCl) in single-molecule magnetic tweezers experiments. This behavior contrasts with that of control protein GB1, which unfolds faster under the same denaturing conditions. Steered molecular dynamics (SMD) simulations indicate that stretching force applied to the N- and C-termini of Csp triggers an allosteric conformational change, converting loop regions into β-strands and reducing the solvent-accessible surface area (SASA). The combination of experimental and simulation data suggests that the unfolding transition state of Csp has a smaller SASA than that of the native state, providing a structural explanation for the observed kinetic anomaly. These results demonstrate that allosteric conformational or dynamical changes, triggered by mechanical or chemical perturbations, can render proteins resistant to denaturation by lowering their unfolding rates, thereby conferring resistance to environmental stress.

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Also Worth Reading

Identification of Bioactive Ingredients and Mechanistic Pathways of Xuefu Zhuyu Decoction in Ventricular Remodeling: A Network Pharmacology, Molecular Docking and Molecular Dynamics Simulations.

Background Xuefu Zhuyu Decoction (XFZYD) is clinically used in China to promote blood circulation, resolve blood stasis, and alleviate ventricular remodeling (VR). However, its molecular mechanisms remain unclear. Objective This study investigates the active components and underlying molecular mechanisms of XFZYD in treating VR. Methods Targets of XFZYD’s active components and VR-related targets were identified. A protein-protein interaction (PPI) network and a drug-ingredient-target network were constructed. GO functional annotation and KEGG pathway enrichment analysis were performed to explore biological functions. Hub targets and their corresponding active ingredients were validated through molecular docking and molecular dynamics (MD) simulations. Results A total of 1,089 active ingredients with high gastrointestinal absorption (GI) and drug-likeness (DL ≥ 2) were identified. Five hundred and thirty-eight common targets were shared between XFZYD and VR, with 10 core targets, including AKT1, STAT3, TP53, EGFR, SRC, TNF, MAPK3, CTNNB1, IL6, and VEGFA. GO analysis revealed XFZYD’s influence on wound healing, oxygen response, epithelial cell proliferation, and receptor signaling. KEGG analysis highlighted key pathways such as PI3K-Akt signaling, lipid and atherosclerosis, and fluid shear stress. Molecular docking revealed that active ingredients display favorable interactions with the hub genes, with binding energies from -9.5 to -6.0 kcal/mol. These interactions were further validated through MD simulations, demonstrating stable binding throughout the 100 ns simulation period. Conclusion XFZYD exhibits therapeutic effects on VR through multiple active components and pathways, providing a scientific basis for its clinical application and further research.

scDock: Streamlining drug discovery targeting cell-cell communication via scRNA-seq analysis and molecular docking.

Summary Identifying drugs that target intercellular communication networks represents a promising therapeutic strategy, yet linking single-cell RNA sequencing (scRNA-seq) analysis to structure-based drug screening remains technically challenging and requires substantial bioinformatics expertise. We present scDock, an integrated and user-friendly pipeline that seamlessly connects scRNA-seq data processing, cell-cell communication inference, and molecular docking-based drug discovery. Through a single configuration file, users can execute the complete workflow, from raw scRNA-seq data to ranked drug candidates, without programming skills. scDock automates the identification of disease-relevant ligand-receptor interactions from scRNA-seq data and performs structure-based virtual screening against these communication targets using Protein Data Bank (PDB) or AlphaFold-predicted protein structures. The pipeline generates comprehensive outputs at each stage, enabling users to explore intercellular signaling alterations and discover therapeutic compounds targeting specific cell-cell communications. scDock addresses a critical gap by providing an accessible end-to-end solution for communication-targeted drug discovery from single-cell data. Availability and implementation scDock is freely available at https://doi.org/10.6084/m9.figshare.31370368 and https://github.com/Andrewneteye4343/scDock. It is implemented in R, Python, shell scripts, and supports Linux systems, including Ubuntu and Debian. Supplementary information Supplementary data are available at Bioinformatics online.

In silico analysis of <i>Anacardium occidentale</i> phytochemicals: pharmacokinetics, molecular docking, and dynamics of <i>Cryptococcus neoformans</i> enzymes.

This study evaluated in silico the antifungal potential of phytochemicals from the leaves of Anacardium occidentale (cashew tree) against key enzymatic targets: farnesyltransferase (CnFTase), beta-carbonic anhydrase (β-CA), and adenylosuccinate synthetase (AdSS) from Cryptococcus neoformans . Molecular docking simulations were conducted to evaluate the binding affinity of selected compounds to key enzymatic targets. The protein structures were retrieved from the Protein Data Bank (PDB) and prepared using AutoDockTools™, while molecular docking was performed with AutoDockVina. Molecular dynamics simulation was performed using the iMODS server, in order to check the stability as well as mobility in the receptor-ligand complexes following molecular docking. Additionally, ADME-Tox properties were predicted using a consensus approach combining ADMETlab 3.0 and ADMET-AI, assessing parameters such as permeability (PAMPA), metabolism (CYP450), and clearance ( Cl int, u , Cl Micro , Cl Hepa ). The structural complexity of the ligands was analyzed using the MCE18 score, allowing the identification of compounds with an optimal balance between drug-likeness and synthetic accessibility. Notably, quercetin 3-galactoside, tricetin 3’-xyloside, and kaempferol 4’-glucoside exhibited favorable pharmacokinetic profiles and docking affinities, suggesting their potential as antifungal candidates. A PAMPA profile is estimated for these compounds based on a moderate permeability in more selective cells (High Papp MDCK) and low hepatic clearance, resulting from metabolic stability. Molecular docking studies showed that lead compounds have excellent affinity and specificity for the enzymes CnFTase and AdSS (affinity energy Cryptococcus neoformans . Supplementary information The online version contains supplementary material available at 10.1007/s40203-026-00590-y.

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Anomalous Effect of Denaturant on Protein Unfolding Dynamics Revealed by Single Molecule Manipulation Experiments.

High temperatures and chemical denaturants in bulk experiments, as well as mechanical forces in single-molecule studies, typically promote protein unfolding. Read more →

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Employ HADDOCK for ambiguous restraints in protein-protein docking.

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