Prion and water: Tight and dynamical hydration sites have a key role in structural stability

Simone, Alfonso De; Dodson, Guy; Verma, Chandra; Zagari, Adriana; Fraternali, Franca

doi:10.1073/pnas.0501748102

Cited by 143 publications

(167 citation statements)

References 36 publications

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“…The analysis of huPrP and shPrP hydration [17] showed a good correlation between MDHS with high residence time (>1 ns) and the crystallographically observed water molecules that are conserved among the known X-ray structures. One of these waters (W1) is of particular interest because it bridges three protein regions belonging to different secondary structural elements (b1, b2 and H3).…”

Section: Structurally Conserved Waters In Prpsmentioning

confidence: 99%

“…Our hydration analysis is largely based on the solvent density map [17,26,27] whose maxima are assumed to be the molecular dynamics hydration sites (MDHS). The space surrounding the protein is divided in two shells: the first describes the water around the protein and comprises the region within a distance of 0.6 nm from the protein surface.…”

Section: Water Density Functionmentioning

confidence: 99%

“…Interestingly, solvent environment has been showed to tune the amyloidogenesis of insulin [16]. In a previous study, based on molecular dynamics (MD) simulations, we pointed out the special hydration properties at the surface of the human (huPrP) and sheep (shPrP) prions [17]. The calculations characterized protein surfaces where tightly bound waters (referred as to ''sharp spots'') evidently add to the local structural stability.…”

Section: Introductionmentioning

confidence: 99%

“…Equally the hydration maps identified specific surfaces where main chain H-bonds are surrounded by very mobile bulk-like water (referred as to ''smooth spots''). These regions might exhibit energetically close alternative patterns of H-bonding effectively modulating the local structural stability and thereby favoring unfolding and aggregation events [17].…”

Section: Introductionmentioning

confidence: 99%

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Water molecules as structural determinants among prions of low sequence identity

Simone¹,

Dodson

Fraternali

et al. 2006

FEBS Letters

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Section: Structurally Conserved Waters In Prpsmentioning

confidence: 99%

Section: Water Density Functionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Water molecules as structural determinants among prions of low sequence identity

Simone¹,

Dodson

Fraternali

et al. 2006

FEBS Letters

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“…Free energy calculations and MD simulations successfully predict the hydration state of pockets of different chemical natures (polar vs nonpolar) 22,50,51,53 , help to understand the relation between internal hydration and function as in the case of charge separation processes [54][55][56][57] , ligand binding [58][59][60] , allostery 61,62 and can be used to estimate the contribution to stability 50,63 .…”

Section: Introductionmentioning

confidence: 99%

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

et al. 2014

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In this work we address the question whether the enhanced stability of thermophilic proteins has a direct connection with internal hydration. Our model systems are two homologues G-domains of different stability: the mesophilic G domain of the Elongation-Factor thermal unstable protein from E. coli and the hyperthermophilic G domain of the EF-α protein from S. solfataricus. Using molecular dynamics simulation at the microsecond time-scale we show that both proteins host water molecules in internal cavities and that these molecules exchange with the external solution in the nanosecond time scale. The hydration free energy of these sites evaluated via extensive calculations is found to be favourable for both systems, with the hyperthermophilic protein offering a slightly more favourable environment to host water molecules. We estimate that under ambient conditions, the free energy gain due to internal hydration is about 1.3 kcal/mol in favor of the hyperthermophilic variant. However, we also find that at the high working temperature of the hyperthermophile, the cavities are rather dehydrated, meaning that at extreme conditions other molecular factors secure the stability of the protein. Interestingly, we detect a clear correlation between the hydration of internal cavities and the protein conformational landscape. The emerging picture is that internal hydration is an effective observable to probe the conformational landscape of proteins. In the specific context of our investigation, the analysis confirms that the hyperthermophilic G-domain is characterized by multiple states and it has a more flexible structure than its mesophilic homologue.

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Hydrophobic Association and Volume‐Confined Water Molecules

Baron¹,

Setny²,

McCammon³

2012

Protein‐Ligand Interactions

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Prion and water: Tight and dynamical hydration sites have a key role in structural stability

Cited by 143 publications

References 36 publications

Water molecules as structural determinants among prions of low sequence identity

Water molecules as structural determinants among prions of low sequence identity

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

Hydrophobic Association and Volume‐Confined Water Molecules

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