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Experimental free energy surfaces reveal the mechanisms of maintenance of protein solubility.

ABSTRACT: The identification of the factors that enable normally folded proteins to remain in their soluble and functional states is crucial for a comprehensive understanding of any biological system. We have determined a series of energy landscapes of the acylphosphatase from Drosophila melanogaster under a variety of conditions by combining NMR measurements with restrained molecular dynamics simulations. We thus analyzed the differences in the structures, dynamics, and energy surfaces of the protein in its soluble state or in situations where it aggregates through conformational states that have native-like structure, folding stability, and enzymatic activity. The study identifies the nature of the energy barriers that under normal physiological conditions prevent the protein ensemble from populating dangerous aggregation-prone states. We found that such states, although similar to the native conformation, have altered surface charge distribution, alternative topologies of the ?-sheet region, and modified solvent exposure of hydrophobic surfaces and aggregation-prone regions of the sequence. The identified barriers allow the protein to undergo functional dynamics while remaining soluble and without a significant risk of misfolding and aggregation into nonfunctional and potentially toxic species.

SUBMITTER: De Simone A

PROVIDER: S-EPMC3248487 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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Experimental free energy surfaces reveal the mechanisms of maintenance of protein solubility.

De Simone Alfonso A Dhulesia Anne A Soldi Gemma G Vendruscolo Michele M Hsu Shang-Te Danny ST Chiti Fabrizio F Dobson Christopher M CM

Proceedings of the National Academy of Sciences of the United States of America 20111212 52

The identification of the factors that enable normally folded proteins to remain in their soluble and functional states is crucial for a comprehensive understanding of any biological system. We have determined a series of energy landscapes of the acylphosphatase from Drosophila melanogaster under a variety of conditions by combining NMR measurements with restrained molecular dynamics simulations. We thus analyzed the differences in the structures, dynamics, and energy surfaces of the protein in ...[more]

PMID: 22160682

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Project description:BackgroundThe database of protein structures contains representatives from organisms with a range of growth temperatures. Various properties have been studied in a search for the molecular basis of protein adaptation to higher growth temperature. Charged groups have emerged as key distinguishing factors for proteins from thermophiles and mesophiles.ResultsA dataset of 291 thermophile-derived protein structures is compared with mesophile proteins. Calculations of electrostatic interactions support the importance of charges, but indicate that increases in charge contribution to folded state stabilisation do not generally correlate with the numbers of charged groups. Relative propensities of charged groups vary, such as the substitution of glutamic for aspartic acid sidechains. Calculations suggest an energetic basis, with less dehydration for longer sidechains. Most other properties studied show weak or insignificant separation of proteins from moderate thermophiles or hyperthermophiles and mesophiles, including an estimate of the difference in sidechain rotameric entropy upon protein folding. An exception is increased burial of alanine and proline residues and decreased burial of phenylalanine, methionine, tyrosine and tryptophan in hyperthermophile proteins compared to those from mesophiles.ConclusionSince an increase in the number of charged groups for hyperthermophile proteins is separable from charged group contribution to folded state stability, we hypothesise that charged group propensity is important in the context of protein solubility and the prevention of aggregation. Accordingly we find some separation between mesophile and hyperthermophile proteins when looking at the largest surface patch that does not contain a charged sidechain. With regard to our observation that aromatic sidechains are less buried in hyperthermophile proteins, further analysis indicates that the placement of some of these groups may facilitate the reduction of folding fluctuations in proteins of the higher growth temperature organisms.

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Experimental free energy surfaces reveal the mechanisms of maintenance of protein solubility.

Publications

Experimental free energy surfaces reveal the mechanisms of maintenance of protein solubility.

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