Temperature-Dependent Coarse-Grained Model for Simulations of Intrinsically Disordered Protein LCST and UCST Liquid–Liquid Phase Separations DOI

Yingmin Jiang,

Tâp Ha‐Duong

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

Published: April 25, 2025

Many intrinsically disordered proteins (IDPs) can undergo a liquid-liquid phase separation (LLPS) in water, depending on solution conditions (temperature, pH, and ionic strength). There are two types of LLPS that controlled by temperature: those occurring above lower critical temperature (LCST) below an upper (UCST). IDP coarse-grained (CG) models particularly appropriate for investigating the physical chemical factors govern their supramolecular organization. However, development CG allowing simulations both LCST UCST behavior temperature-sensitive IDPs is still its infancy. In this context, we present here novel temperature-dependent (TD) model based MARTINI 3 force field. The was developed modifying Lennard-Jones potentials between apolar or charged solute beads water with TD rescaling factor. It parametrized to fit mean (PMF) molecules computed using all-atom (AA) simulations. We show able reproduce experimentally known low-complexity sequences estimate transition temperatures comparable experimental measurements.

Language: Английский

New Approach for Targeting Small Molecule Candidates for Intrinsically Disordered Proteins DOI
Milan Senćanski

Published: April 23, 2025

Intrinsically disordered proteins (IDPs), like the Alzheimer’s associated tau protein, pose challenges for conventional drug discovery. This study applied Informational Spectrum Method Small Molecules (ISM-SM), a computational technique utilising electron-ion interaction potentials (EIIP), to identify potential modulators. Characteristic frequencies derived from known ligands and conserved mammalian sequences were used screen DrugBank COCONUT natural product database. The screening identified approved drugs previously reported indirectly influence pathology or disease pathways, alongside products Bryostatin-14, modulate kinases involved in phosphorylation. These findings suggest ISM-SM can serve as an silico tool candidate small molecules, including repurposed products, with relevance function pathology, complementing other IDP discovery strategies.

Language: Английский

Citations

0
Temperature-Dependent Coarse-Grained Model for Simulations of Intrinsically Disordered Protein LCST and UCST Liquid–Liquid Phase Separations DOI

Yingmin Jiang,

Tâp Ha‐Duong

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

Published: April 25, 2025

Many intrinsically disordered proteins (IDPs) can undergo a liquid-liquid phase separation (LLPS) in water, depending on solution conditions (temperature, pH, and ionic strength). There are two types of LLPS that controlled by temperature: those occurring above lower critical temperature (LCST) below an upper (UCST). IDP coarse-grained (CG) models particularly appropriate for investigating the physical chemical factors govern their supramolecular organization. However, development CG allowing simulations both LCST UCST behavior temperature-sensitive IDPs is still its infancy. In this context, we present here novel temperature-dependent (TD) model based MARTINI 3 force field. The was developed modifying Lennard-Jones potentials between apolar or charged solute beads water with TD rescaling factor. It parametrized to fit mean (PMF) molecules computed using all-atom (AA) simulations. We show able reproduce experimentally known low-complexity sequences estimate transition temperatures comparable experimental measurements.

Language: Английский

Citations

0