Deciphering the Mystery in p300 Taz2–p53 TAD2 Recognition DOI
Tongtong Li, Stefano Motta, Yi He

et al.

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 14, 2024

Intrinsically disordered proteins (IDPs) engage in various fundamental biological activities, and their behavior is of particular importance for a better understanding the verbose but well-organized signal transduction cells. IDPs exhibit uniquely paradoxical features with low affinity simultaneously high specificity recognizing binding targets. The transcription factor p53 plays crucial role cancer suppression, carrying out some its functions using regions, such as N-terminal transactivation domain 2 (TAD2). Exploration unbinding processes between challenging, inherently properties these regions further complicate issue. Computer simulations are powerful tool to complement experiments fill gaps explore binding/unbinding proteins. Here, we investigated mechanism p300 Taz2 TAD2 through extensive molecular dynamics (MD) physics-based UNited RESidue (UNRES) force field additional Go̅-like potentials. Distance restraints extracted from NMR-resolved structures were imposed on intermolecular residue pairs accelerate simulations, which was immobilized native-like conformation fully free. Starting six placed at different positions around Taz2, observed metastable intermediate state middle helical segment anchored pocket, highlighting significance helix directing protein recognition. Physics-based show that successful achieved after series stages, including (1) collisions initiate formation encounter complexes, (2) partial attachment TAD2, finally (3) full correct pocket Taz2. Furthermore, machine-learning-based PathDetect-SOM used identify two pathways, states.

Language: Английский

CREST—A program for the exploration of low-energy molecular chemical space DOI Creative Commons
Philipp Pracht, Stefan Grimme, Christoph Bannwarth

et al.

The Journal of Chemical Physics, Journal Year: 2024, Volume and Issue: 160(11)

Published: March 21, 2024

Conformer–rotamer sampling tool (CREST) is an open-source program for the efficient and automated exploration of molecular chemical space. Originally developed in Pracht et al. [Phys. Chem. Phys. 22, 7169 (2020)] as driver calculations at extended tight-binding level (xTB), it offers a variety molecular- metadynamics simulations, geometry optimization, structure analysis capabilities. Implemented algorithms include procedures conformational sampling, explicit solvation studies, calculation absolute entropy, identification protonation deprotonation sites. Calculations are set up to run concurrently, providing single-node parallelization. CREST designed require minimal user input comes with implementation GFNn-xTB Hamiltonians GFN-FF force-field. Furthermore, interfaces any quantum chemistry force-field software can easily be created. In this article, we present recent developments code show selection applications most important features program. An novelty refactored backend, which provides significant speed-up small or medium-sized drug molecules allows more sophisticated setups, example, mechanics/molecular mechanics minimum energy crossing point calculations.

Language: Английский

Citations

92
Decoding Solubility Signatures from Amyloid Monomer Energy Landscapes DOI Creative Commons
Patryk A. Wesołowski,

Bojun Yang,

Anthony J. Davolio

et al.

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

This study investigates the energy landscapes of amyloid monomers, which are crucial for understanding protein misfolding mechanisms in Alzheimer's disease. While proteins possess inherent thermodynamic stability, environmental factors can induce deviations from native folding pathways, leading to and aggregation, phenomena closely linked solubility. Using UNOPTIM program, integrates UNRES potential into Cambridge landscape framework, we conducted single-ended transition state searches employed discrete path sampling compute kinetic networks starting PDB structures. These consist local minima states that connect them, quantify monomers. We defined clusters within each using thresholds selected their lowest-energy structures structural analysis. Applying graph convolutional networks, identified solubility trends correlated them with features. Our findings identify specific low solubility, characteristic aggregation-prone states, highlighting key residues drive reduced Notably, exposure hydrophobic residue Phe19 solvent triggers a collapse by disrupting neighboring helix. Additionally, investigated determine first passage times between thereby elucidating kinetics these landscapes. comprehensive approach provides valuable insights thermodynamics Aβ By integration multiple analytical techniques explore landscapes, our features associated have inform future therapeutic strategies aimed at addressing aggregation neurodegenerative diseases.

Language: Английский

Citations

0
Overview on Building Blocks and Applications of Efficient and Robust Extended Tight Binding DOI
Abylay Katbashev, Marcel Stahn, Thomas Rose

et al.

The Journal of Physical Chemistry A, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

The extended tight binding (xTB) family of methods opened many new possibilities in the field computational chemistry. Within just 5 years, GFN2-xTB parametrization for all elements up to Z = 86 enabled more than a thousand applications, which were previously not feasible with other electronic structure methods. xTB provide robust and efficient way apply quantum mechanics-based approaches obtaining molecular geometries, computing free energy corrections or describing noncovalent interactions found applicability targets. A crucial contribution success is availability within simulation packages frameworks, supported by open source development its program library packages. We present comprehensive summary applications capabilities different fields Moreover, we consider main software calculations, covering their current ecosystem, novel features, usage scientific community.

Language: Английский

Citations

0
Conformational Pruning via the Permutation Invariant Root-Mean-Square Deviation of Atomic Positions DOI
Philipp Pracht

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

The Cartesian root-mean-square deviation (RMSD) of atomic coordinates is fundamental for comparing three-dimensional molecular structures, particularly in identifying and classifying conformations. Since properties are determined by the conformation, pruning duplicates via a structural similarity metric like RMSD will reduce redundant calculations hence directly impact cost automated workflows computational chemistry. However, traditional struggles when dealing with local symmetry molecules atom permutation, often leading to inflated errors inefficiency. This work addresses these challenges providing clear definitions within conformational ensembles developing an efficient divide-and-conquer algorithm their distinction. proposed permutation invariant (iRMSD) approach efficiently overcomes associated symmetric multiple rotamers incorporating procedure that assigns canonical identities optimizes atom-to-atom assignment process. leads significant reductions complexity, making method highly suitable rapid, large-scale analysis property prediction workflows, both effective duplicate conformations enabling cross-methodology ensemble comparison.

Language: Английский

Citations

0
Exploring the thermodynamics of protein aggregation: an insight to Huntington's disease therapeutics DOI

Rajinder Singh Kaundal,

Tejasvi Pandey, Vivek Pandey

et al.

Neuroscience and Behavioral Physiology, Journal Year: 2024, Volume and Issue: 54(7), P. 1042 - 1060

Published: Aug. 27, 2024

Language: Английский

Citations

1
Guest binding is governed by multiple stimuli in low-symmetry metal-organic cages containing bis-pyridyl(imine) vertices DOI Creative Commons
Yuchong Yang, Tanya K. Ronson, Paula C. P. Teeuwen

et al.

Chem, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

Citations

1
Deciphering the Mystery in p300 Taz2–p53 TAD2 Recognition DOI
Tongtong Li, Stefano Motta, Yi He

et al.

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 14, 2024

Intrinsically disordered proteins (IDPs) engage in various fundamental biological activities, and their behavior is of particular importance for a better understanding the verbose but well-organized signal transduction cells. IDPs exhibit uniquely paradoxical features with low affinity simultaneously high specificity recognizing binding targets. The transcription factor p53 plays crucial role cancer suppression, carrying out some its functions using regions, such as N-terminal transactivation domain 2 (TAD2). Exploration unbinding processes between challenging, inherently properties these regions further complicate issue. Computer simulations are powerful tool to complement experiments fill gaps explore binding/unbinding proteins. Here, we investigated mechanism p300 Taz2 TAD2 through extensive molecular dynamics (MD) physics-based UNited RESidue (UNRES) force field additional Go̅-like potentials. Distance restraints extracted from NMR-resolved structures were imposed on intermolecular residue pairs accelerate simulations, which was immobilized native-like conformation fully free. Starting six placed at different positions around Taz2, observed metastable intermediate state middle helical segment anchored pocket, highlighting significance helix directing protein recognition. Physics-based show that successful achieved after series stages, including (1) collisions initiate formation encounter complexes, (2) partial attachment TAD2, finally (3) full correct pocket Taz2. Furthermore, machine-learning-based PathDetect-SOM used identify two pathways, states.

Language: Английский

Citations

0