Molecular Systems Design & Engineering, Год журнала: 2024, Номер 10(2), С. 89 - 101
Опубликована: Дек. 24, 2024
We develop a physics-informed machine learning workflow that accelerates multicomponent phase-coexistence calculations on the number, composition, and abundance of phases. The is demonstrated for systems described by Flory–Huggins theory.
Язык: Английский
Physical review. E, Год журнала: 2025, Номер 111(5)
Опубликована: Май 8, 2025
Язык: Английский
Процитировано
0
Faraday Discussions, Год журнала: 2024, Номер unknown
Опубликована: Янв. 1, 2024
We investigate three related questions: can we identify the sequence determinants which lead to protein self interactions and phase separation; understand design new sequences selectively bind condensates?; multiphasic condensates?
Язык: Английский
Процитировано
2
The Journal of Chemical Physics, Год журнала: 2024, Номер 161(9)
Опубликована: Сен. 3, 2024
Intrinsically disordered proteins (IDPs) are prevalent participants in liquid–liquid phase separation due to their inherent potential for promoting multivalent binding. Understanding the underlying mechanisms of is challenging, as a complex process, involving numerous molecules and various types interactions. Here, we used simplified coarse-grained model IDPs investigate thermodynamic stability dense phase, conformational properties IDPs, chain dynamics, kinetic rates forming condensates. We focused on IDP system, which oppositely charged maximally segregated, inherently possessing high propensity separation. By varying interaction strengths, salt concentrations, temperatures, observed that exhibited highly conserved characteristics, more extended than those dilute phase. Although motions global dynamics condensates slow viscosity, local flexibility at short timescales largely preserved with respect free state. Strikingly, non-monotonic relationship between strengths As strong interactions result stable condensates, our results suggest thermodynamics kinetics decoupled optimized by speed-stability balance through molecular Our findings contribute molecular-level understanding offer valuable insights into developments engineering strategies precise regulation biomolecular
Язык: Английский
Процитировано
2
Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(50)
Опубликована: Дек. 6, 2024
Understanding the biophysical basis of protein aggregation is important in biology because potential link to several misfolding diseases. Although experiments have shown that aggregates adopt a variety morphologies, dynamics their formation are less well characterized. Here, we introduce minimal model explore dependence on structural and sequence features monomers. Using simulations, demonstrate complexity (codified terms word entropy) monomer rigidity profoundly influence morphology aggregates. Flexible monomers with low (corresponding repeat sequences) form liquid-like droplets exhibit ergodic behavior. Strikingly, these abruptly transition more ordered structures, reminiscent amyloid fibrils, when increased. In contrast, resulting from high amorphous display nonergodic glassy dynamics. The heterogeneous high-complexity sequences follow stretched exponential kinetics, which one characteristics Importantly, at nonzero values bending rigidities, age relaxation times increase waiting time. Informed by findings, provide insights into aging condensates contrast behavior expected RNA sequences. Our findings underscore shaping aggregates, thus providing foundation for deciphering general rules governing condensates.
Язык: Английский
Процитировано
2
Опубликована: Авг. 12, 2024
Understanding how a macromolecule’s primary sequence governs its conformational landscape is crucial for elucidating function, yet these design principles are still emerging macromolecules with intrinsic disorder. Herein, we introduce high-throughput workflow that implements practical colorimetric assay, introduces semi-automated sequencing protocol using MALDI-MS/MS, and develops generalizable sequence-structure algorithm. Using model system of 20mer peptidomimetics containing polar glycine hydrophobic N-butylglycine residues, identified nine classifications disorder isolated 122 unique sequences across varied compositions conformations. Conformational distributions three compositionally identical library were corroborated through atomistic simulations ion mobility spectrometry coupled liquid chromatography. A data-driven strategy was developed existing variables data-derived ‘motifs’ to inform machine learning algorithm towards conformation prediction. This multifaceted approach enhances our understanding sequence-conformation relationships offers powerful tool accelerating the discovery materials control.
Язык: Английский
Процитировано
1
Soft Matter, Год журнала: 2024, Номер 20(31), С. 6150 - 6159
Опубликована: Янв. 1, 2024
The role of charge-asymmetric polyampholytes is unveiled in the liquid–liquid phase separation their mixtures with charge-symmetric polyampholytes.
Язык: Английский
Процитировано
1
Journal of Chemical Information and Modeling, Год журнала: 2024, Номер unknown
Опубликована: Дек. 11, 2024
Macromolecular crowding in the cellular cytoplasm can potentially impact diffusion rates of proteins, their intrinsic structural stability, binding proteins to corresponding partners as well biomolecular organization and phase separation. While such intracellular have a large on structure function, molecular mechanisms driving forces that determine effect dynamics conformations macromolecules are so far not understood. At level, computational methods provide unique lens investigate macromolecular behavior, providing us with resolution is challenging reach experimental techniques alone. In this review, we focus various physics-based data-driven developed past few years protein condensation. We review recent progress modeling simulation systems varying sizes, ranging from single molecules entire cytoplasm. further discuss effects different phenomena, diffusion, protein-ligand binding, mechanical viscoelastic properties, surface tension condensates. Finally, some outstanding challenges anticipate community addressing next order biological phenomena model environments by reproducing
Язык: Английский
Процитировано
1
Опубликована: Июнь 12, 2024
Understanding the biophysical basis of protein aggregation is important in biology because potential link to several misfolding diseases. Although experiments have shown that aggregates adopt a variety morphologies, dynamics their formation are less well characterized. Here, we introduce minimal model explore dependence on structural and sequence features monomers. Using simulations demonstrate complexity (codified terms word entropy) monomer rigidity profoundly influence morphology aggregates. Flexible monomers with low (corresponding repeat sequences) form liquid-like droplets exhibit ergodic behavior. Strikingly, these abruptly transition more ordered structures, reminiscent amyloid fibrils, when increased. In contrast, resulting from high amorphous display non-ergodic glassy dynamics. The heterogeneous high-complexity sequences follow stretched exponential kinetics, which one characteristics Importantly, at non-zero values bending rigidities, age relaxation times increase waiting time. Informed by findings, provide insights into aging condensates contrast behavior expected RNA sequences. Our findings underscore shaping aggregates, thus providing foundation for deciphering general rules governing condensates. Significance Statement Protein diverse morphology, exemplified gel-like Differences morphologies identical proteins play functional roles Simulations using show such structures encoded low-complexity flexible liquid droplets, whose ergodic. rigid sequences, nematic fibril-like heterogenous, under conditions as time increases, signature aging. implications our intrinsically dis-ordered outlined.
Язык: Английский
Процитировано
0
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Сен. 1, 2024
Abstract Enhancers regulate gene expression by forming contacts with distant promoters. Phase-separated condensates or clusters formed transcription factors (TFs) and co-factors are thought to facilitate these enhancer-promoter (E-P) interactions. Using polymer physics, we developed distinct coarse-grained chromatin models that produce similar ensemble-averaged Hi-C maps but “stable” “dynamic” characteristics. Our findings, consistent recent experiments, reveal a multi-step E-P communication process. The dynamic model facilitates proximity enhancing TF clustering subsequently promotes direct interactions destabilizing the through chain flexibility. study physical understanding of molecular mechanisms governing in transcriptional regulation. Graphical TOC Entry
Язык: Английский
Процитировано
0
Chem, Год журнала: 2024, Номер 10(11), С. 3444 - 3458
Опубликована: Сен. 6, 2024
Язык: Английский
Процитировано
0