Effects of Molecular Crowding on the Dynamics of Intrinsically Disordered Proteins

Cino, Elio A.; Karttunen, Mikko; Choy, Wing‐Yiu

doi:10.1371/journal.pone.0049876

Cited by 89 publications

(99 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A comprehensive view brings into consideration the existence of different LEA4 conformers in equilibrium (partially folded or unfolded) under crowded or water-deficit environments, which supports the existence of preformed secondary structural elements, denominated as prestructured motifs that could be implicated in the recognition of different and specific binding partners (56). Our findings strongly suggest that water deficit leads to the stabilization of particular conformations in group 4 LEA proteins that may allow the exposure of different motifs necessary for the binding of their target molecules, hence supporting the idea that LEA proteins of this group function as a structural ensemble, whose dynamism can be modulated by environmental conditions (57)(58)(59)(60). This proposed mode of action also exhibits possible binding promiscuity, in consonance with their role as chaperone-like molecules needed during water scarcity.…”

Section: Discussionsupporting

confidence: 79%

The Unstructured N-terminal Region of Arabidopsis Group 4 Late Embryogenesis Abundant (LEA) Proteins Is Required for Folding and for Chaperone-like Activity under Water Deficit

Cuevas-Velazquez

Saab‐Rincón

Reyes

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Late embryogenesis abundant (LEA) proteins are a conserved group of proteins widely distributed in the plant kingdom that participate in the tolerance to water deficit of different plant species. In silico analyses indicate that most LEA proteins are structurally disordered. The structural plasticity of these proteins opens the question of whether water deficit modulates their conformation and whether these possible changes are related to their function. In this work, we characterized the secondary structure of Arabidopsis group 4 LEA proteins. We found that they are disordered in aqueous solution, with high intrinsic potential to fold into ␣-helix. We demonstrate that complete dehydration is not required for these proteins to sample ordered structures because milder water deficit and macromolecular crowding induce high ␣-helix levels in vitro, suggesting that prevalent conditions under water deficit modulate their conformation. We also show that the N-terminal region, conserved across all group 4 LEA proteins, is necessary and sufficient for conformational transitions and that their protective function is confined to this region, suggesting that folding into ␣-helix is required for chaperone-like activity under water limitation. We propose that these proteins can exist as different conformers, favoring functional diversity, a moonlighting property arising from their structural dynamics.

show abstract

Section: Discussionsupporting

confidence: 79%

The Unstructured N-terminal Region of Arabidopsis Group 4 Late Embryogenesis Abundant (LEA) Proteins Is Required for Folding and for Chaperone-like Activity under Water Deficit

Cuevas-Velazquez

Saab‐Rincón

Reyes

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This would also explain why the s 2 and RMSF profiles determined under crowded conditions are not too different from those observed in water, both in simulations and in experimental data, 58,65,66 with only mild reductions in the flexibility of loops but almost no effect on the structured regions. As a corollary, future experimental investigations on the effect of cosolvents or crowding on internal dynamics should look for differences in microsecond and slower time scales, for example, through deuterium exchange or relaxation dispersion NMR experiments.…”

Section: ■ Discussionmentioning

confidence: 77%

Dissecting the Effects of Concentrated Carbohydrate Solutions on Protein Diffusion, Hydration, and Internal Dynamics

et al. 2014

View full text Add to dashboard Cite

We present herein a thorough description of the effects of high glucose concentrations on the diffusion, hydration and internal dynamics of ubiquitin, as predicted from extensive molecular dynamics simulations on several systems described at fully atomistic level. We observe that the protein acts as a seed that speeds up the natural propensity of glucose to cluster at high concentration; the sugar molecules thus aggregate around the protein trapping it inside a dynamic cage. This process extensively dehydrates the protein surface, restricts the motions of the remaining water molecules, and drags the large-scale, collective motions of protein atoms slowing down the rate of exploration of the conformational space despite only a slight dampening of fast, local dynamics. We discuss how these effects could be relevant to the function of sugars as preservation agents in biological materials, and how crowding by small sticky molecules could modulate proteins across different reaction coordinates inside the cellular cytosol. ■ INTRODUCTIONSugars play roles as agents for the preservation of biological material in nature and in biotechnological manufacture, 1−3 most importantly through their capacity to stabilize proteins against cold and hot denaturation, both in solution and in the solid state. 4−7 Other potential effects of sugars on protein properties have been less explored, but changes in activity, dynamics, and regulation can be expected by analogy to the effects known to be caused by high concentrations of other molecules. Whereas most hydrophilic molecules have the capacity to agglomerate and disrupt water structure, sugars and polyols generally have exceptionally large solubilities, which allows them to strongly dehydrate other molecules and to cluster at very high concentrations forming glassy states. 8−11 Because of these special properties, questions about the effects of sugars on protein properties are intimately related to those revolving around the effects of viscosity, molecular crowding, encapsulation and even vitrification on proteins, all meeting at the crossroads between chemistry, biology, medicine, and applications in the food and pharmacological industries. Within all these closely related fields, the effects of high concentrations of small hydrophilic molecules on protein stability and translational and rotational diffusion have been explored, but studies of their effects on protein hydration and on internal protein dynamics are scarce. 4−7,12−16 More specifically to sugars, reports on the structure and dynamics of sugar-only solutions abound, 8,17−23 but works dealing with proteins in sugar solutions are mostly focused on the stability of the proteins and do not pay much attention to other effects related to hydration, diffusion, and internal mobility. 4−7 We recently reported in a preliminary work that concentrated glucose solutions can perturb protein dynamics by restricting exploration of the conformational space, through a mechanism that presumably involves protein−sugar interac...

show abstract

“…For example, obstruction is a many-body problem and in general a numerical solution of the obstruction factor is the only practicable approach. MD simulations for these systems can provide valuable information on the solute-solute, solvent-solvent and solute-solvent interactions at the atomic level [37,38,[74][75][76].…”

Section: Obstructionmentioning

confidence: 99%

“…Amino acids, being simpler than proteins, are a logical stepping stone toward understanding crowded biological systems. The clustering of amino acids such as glycine has been studied using NMR diffusion experiments and molecular dynamics (MD) simulations as a function of concentration, pH and temperature [22][23][24][34][35][36][37][38]. Hughes et al [23] used a multidisciplinary approach (i.e., NMR diffusion, MD simulations and small-angle neutron scattering) to investigate the crystallization of glycine in aqueous solutions.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Macromolecular crowding studies of amino acids using NMR diffusion measurements and molecular dynamics simulations

et al. 2015

View full text Add to dashboard Cite

Molecular crowding occurs when the total concentration of macromolecular species in a solution is so high that a considerable proportion of the volume is physically occupied and therefore not accessible to other molecules. This results in significant changes in the solution properties of the molecules in such systems. Macromolecular crowding is ubiquitous in biological systems due to the generally high intracellular protein concentrations. The major hindrance to understanding crowding is the lack of direct comparison of experimental data with theoretical or simulated data. Self-diffusion is sensitive to changes in the molecular weight and shape of the diffusing species, and the available diffusion space (i.e., diffusive obstruction). Consequently, diffusion measurements are a direct means for probing crowded systems including the self-association of molecules. In this work, nuclear magnetic resonance (NMR) measurements of the self-diffusion of four amino acids (glycine, alanine, valine and phenylalanine) up to their solubility limit in water were compared directly with molecular dynamics simulations. The experimental data were then analyzed using various models of aggregation and obstruction. Both experimental and simulated data revealed that the diffusion of both water and the amino acids were sensitive to the amino acid concentration. The direct comparison of the simulated and experimental data afforded greater insights into the aggregation and obstruction properties of each amino acid.

show abstract

Effects of Molecular Crowding on the Dynamics of Intrinsically Disordered Proteins

Cited by 89 publications

References 92 publications

The Unstructured N-terminal Region of Arabidopsis Group 4 Late Embryogenesis Abundant (LEA) Proteins Is Required for Folding and for Chaperone-like Activity under Water Deficit

The Unstructured N-terminal Region of Arabidopsis Group 4 Late Embryogenesis Abundant (LEA) Proteins Is Required for Folding and for Chaperone-like Activity under Water Deficit

Dissecting the Effects of Concentrated Carbohydrate Solutions on Protein Diffusion, Hydration, and Internal Dynamics

Macromolecular crowding studies of amino acids using NMR diffusion measurements and molecular dynamics simulations

Contact Info

Product

Resources

About