Metastable States in the Hinge-Bending Landscape of an Enzyme in an Atomistic Cytoplasm Simulation

Samuel Russell, Premila P.; Maytin, Andrew K.; Rickard, Meredith M.; Russell, Matthew C.; Pogorelov, Taras V.; Gruebele, Martin

doi:10.1021/acs.jpclett.3c03134

Cited by 2 publications

(2 citation statements)

References 41 publications

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“…Macromolecular crowding can influence the structural equilibrium of proteins, 1–3 but the precise nature of the change is difficult to predict. Since cellular environments are highly crowded, understanding the effects of macromolecular crowding on protein structure is crucial to understanding protein function in a cellular context.…”

Section: Introductionmentioning

confidence: 99%

“…Many well-folded proteins function through transitions between conformational states; hence, crowding can also affect their function via changes to their conformational equilibrium. 1,3 For instance, crowding influences the function of the bacterial transcription initiation complex, which exerts its function through conformational changes. 48,49 However, studies reporting crowding-induced changes in folded proteins with a predominant conformation indicate, at most, a modest change in structure.…”

Section: Introductionmentioning

confidence: 99%

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PEG-mCherry interactions beyond classical macromolecular crowding

Haas-Neill,

Joron,

Lerner

et al. 2024

Preprint

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The dense cellular environment influences bio-macromolecular structure, dynamics, interactions and function. Despite advancements in understanding protein-crowder interactions, predicting their precise effects on protein structure and function remains challenging. Here, we elucidate the effects of PEG-induced crowding on the fluorescent protein mCherry using molecular dynamics simulations and fluorescence-based experiments. We identify and characterize specific PEG-induced structural and dynamical changes in mCherry. Importantly, we find interactions in which PEG molecules wrap around specific surface-exposed residues in a binding mode previously observed in protein crystal structures. Fluorescence correlation spectroscopy experiments capture PEG-induced changes, including aggregation, suggesting a potential role for the specific PEG-mCherry interactions identified in simulations. Additionally, mCherry fluorescence lifetimes are influenced by PEG and not by the bulkier crowder dextran, highlighting the importance of crowder-protein soft interactions. This work augments our understanding of macromolecular crowding effects on protein structure and dynamics.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PEG-mCherry interactions beyond classical macromolecular crowding

Haas-Neill,

Joron,

Lerner

et al. 2024

Preprint

View full text Add to dashboard Cite

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Recent Progress in Modeling and Simulation of Biomolecular Crowding and Condensation Inside Cells

Mathur,

Ghosh,

Nunes-Alves

2024

J. Chem. Inf. Model.

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Macromolecular crowding in the cellular cytoplasm can potentially impact diffusion rates of proteins, their intrinsic structural stability, binding of proteins to their corresponding partners as well as biomolecular organization and phase separation. While such intracellular crowding can have a large impact on biomolecular structure and function, the molecular mechanisms and driving forces that determine the effect of crowding on dynamics and conformations of macromolecules are so far not well understood. At a molecular level, computational methods can provide a unique lens to investigate the effect of macromolecular crowding on biomolecular behavior, providing us with a resolution that is challenging to reach with experimental techniques alone. In this review, we focus on the various physics-based and data-driven computational methods developed in the past few years to investigate macromolecular crowding and intracellular protein condensation. We review recent progress in modeling and simulation of biomolecular systems of varying sizes, ranging from single protein molecules to the entire cellular cytoplasm. We further discuss the effects of macromolecular crowding on different phenomena, such as diffusion, protein−ligand binding, and mechanical and viscoelastic properties, such as surface tension of condensates. Finally, we discuss some of the outstanding challenges that we anticipate the community addressing in the next few years in order to investigate biological phenomena in model cellular environments by reproducing in vivo conditions as accurately as possible.

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Metastable States in the Hinge-Bending Landscape of an Enzyme in an Atomistic Cytoplasm Simulation

Cited by 2 publications

References 41 publications

PEG-mCherry interactions beyond classical macromolecular crowding

PEG-mCherry interactions beyond classical macromolecular crowding

Recent Progress in Modeling and Simulation of Biomolecular Crowding and Condensation Inside Cells

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