Dynamics of Hydration Water around Native and Misfolded α-Lactalbumin

Brotzakis, Z. Faidon; Groot, C. C. M.; Brandeburgo, Wagner Homsi; Bakker, Huib J.; Bolhuis, Peter G.

doi:10.1021/acs.jpcb.6b02592

Cited by 40 publications

(47 citation statements)

References 37 publications

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“…A direct relationship has been established between the approach of a new H-bond acceptor and the excluded volume effect induced by local confinement and/or the presence of hydrophobic groups. Accordingly, it has been suggested that PW H-bonds near convex protein sites break via angular jump mechanism, whereas near the concave (buried) sites, the breaking of H-bonds is likely to occur via diffusion (70,80). In line with these previous studies, our analysis revealed an association between the stronger confinement and the restrained dynamics of hydration water near the NAC domain.…”

Section: Molecular Origin Of Dynamical Heterogeneity In Hydration Shellsupporting

confidence: 88%

Femtosecond Hydration Map of Intrinsically Disordered α-Synuclein

Arya

Singh

Bhasne

et al. 2018

Biophysical Journal

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Protein hydration water plays a fundamentally important role in protein folding, binding, assembly, and function. Little is known about the hydration water in intrinsically disordered proteins that challenge the conventional sequence-structure-function paradigm. Here, by combining experiments and simulations, we show the existence of dynamical heterogeneity of hydration water in an intrinsically disordered presynaptic protein, namely α-synuclein, implicated in Parkinson's disease. We took advantage of nonoccurrence of cysteine in the sequence and incorporated a number of cysteine residues at the N-terminal segment, the central amyloidogenic nonamyloid-β component (NAC) domain, and the C-terminal end of α-synuclein. We then labeled these cysteine variants using environment-sensitive thiol-active fluorophore and monitored the solvation dynamics using femtosecond time-resolved fluorescence. The site-specific femtosecond time-resolved experiments allowed us to construct the hydration map of α-synuclein. Our results show the presence of three dynamically distinct types of water: bulk, hydration, and confined water. The amyloidogenic NAC domain contains dynamically restrained water molecules that are strikingly different from the water molecules present in the other two domains. Atomistic molecular dynamics simulations revealed longer residence times for water molecules near the NAC domain and supported our experimental observations. Additionally, our simulations allowed us to decipher the molecular origin of the dynamical heterogeneity of water in α-synuclein. These simulations captured the quasi-bound water molecules within the NAC domain originating from a complex interplay between the local chain compaction and the sequence composition. Our findings from this synergistic experimental simulation approach suggest longer trapping of interfacial water molecules near the amyloidogenic hotspot that triggers the pathological conversion into amyloids via chain sequestration, chain desolvation, and entropic liberation of ordered water molecules.

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Section: Molecular Origin Of Dynamical Heterogeneity In Hydration Shellsupporting

confidence: 88%

Femtosecond Hydration Map of Intrinsically Disordered α-Synuclein

Arya

Singh

Bhasne

et al. 2018

Biophysical Journal

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“…To obtain insight in the role of the solvent we analyzed the structural and orientation dynamics of water in the dissociation transition, with the same protocol as in Refs. [48,49].…”

Section: Water Structure and Dynamics Analysismentioning

confidence: 99%

“…10g,h,i). Indeed, the slow population around D33 increases upon association as the formation of the hydrophilic interface provides polar and charged neighbouring amino-acids, e.g R40, as well as a more excluded volume (dry interface) environment [48]. However, in TSR2, there is a temporary increase of fast tetrahedral water, because the second D33 has not (yet) formed a contact with R40, but is exposed to hydrophobic residues I147, I29 and L149.…”

Section: Structure and Dynamics Of Hydration Water During Dissociationmentioning

confidence: 99%

“…However, in TSR2, there is a temporary increase of fast tetrahedral water, because the second D33 has not (yet) formed a contact with R40, but is exposed to hydrophobic residues I147, I29 and L149. Moreover, the smaller dry area of TSR2 compared to N excludes the solvent around the second D33 less, yielding a faster reorientation dynamics and more tetrahedral structure [48].…”

Section: Structure and Dynamics Of Hydration Water During Dissociationmentioning

confidence: 99%

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Unbiased Atomistic Insight in the Mechanisms and Solvent Role for Globular Protein Dimer Dissociation

Brotzakis

Bolhuis

2018

Preprint

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Association and dissociation of proteins are fundamental processes in nature. While this process is simple to understand conceptually, the details of the underlying mechanism and role of the solvent are poorly understood. Here we investigate the mechanism and solvent role for the dissociation of the hydrophilic β-lactoglobulin dimer by employing transition path sampling. Analysis of the sampled path ensembles indicates that dissociation (and association) occurs via a variety of mechanisms: 1) a direct aligned dissociation 2) a hopping and rebinding transition followed by unbinding 3) a sliding transition before unbinding. Reaction coordinate and transition state analysis predicts that, besides native contact and vicinity salt-bridge interactions, solvent degrees of freedom play an important role in the dissociation process. Analysis of the structure and dynamics of the solvent molecules reveals that the dry native interface induces enhanced populations of both disordered hydration water and hydration water with higher tetrahedrality, mainly nearby hydrophobic residues. Bridging waters, hydrogen bonded to both proteins, support contacts, and exhibit a faster decay and reorientation dynamics in the transition state than in the native state interface, which renders the proteins more mobile and assists in rebinding. While not exhaustive, our sampling of rare unbiased reactive molecular dynamics trajectories shows in full detail how proteins can dissociate via complex pathways including (multiple) rebinding events. The atomistic insight obtained assists in further understanding and control of the dynamics of protein-protein interaction including the role of solvent.PACS numbers:

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“…Reciprocally both experimental [9,17] and simulation results [18][19][20] agree on that a protein perturbs the water dynamics in its hydration shell. However the degree and molecular origin of this perturbation are not yet completely understood [4,21]. Water molecules in the protein hydration layer can be considered to be spatially confined.…”

Section: Introductionmentioning

confidence: 99%

Low temperature dependence of protein-water interactions on barstar surface: A nano-scale modelling

Moron

2018

Journal of Molecular Liquids

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The dynamics of the hydration shell of the inhibitor barstar is analysed at low temperature (300-243 K), through all-atom molecular dynamics simulations, and compared with that of bulk water. The relaxation of residence times of solvent molecules in the protein hydration shell follows a stretched exponential function exp[-(t/τ) β ] with β=0.48±0.01, independent of temperature, showing that the decay process is mainly dominated by long-range molecular relaxation channels (short-range for bulk water). The percentage of water molecules exhibiting 4 hydrogen bonds, x HB4 , is found to be a parameter essential for understanding some room and low temperature dependent properties of the protein hydration shell, suggesting an explanation for the unfreezing of protein hydration water as temperature decrease below 273 K. Moreover the dynamical transition that proteins and their hydration water exhibit at ~225 K can be explained by the decrease of 'hydrogen bond defects' in the protein hydration shell as temperature goes down. If most of those water molecules would present a tetrahedral arrangement (nearly no 'hydrogen bond defects'), the bioactivity of proteins would be negligible. Comparison with experimental results is provided all along the work. Experimental data are quantitatively reproduced.

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Dynamics of Hydration Water around Native and Misfolded α-Lactalbumin

Cited by 40 publications

References 37 publications

Femtosecond Hydration Map of Intrinsically Disordered α-Synuclein

Femtosecond Hydration Map of Intrinsically Disordered α-Synuclein

Unbiased Atomistic Insight in the Mechanisms and Solvent Role for Globular Protein Dimer Dissociation

Low temperature dependence of protein-water interactions on barstar surface: A nano-scale modelling

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