Water as a Conformational Editor in Protein Folding

Sessions, Richard B.; Thomas, Geraint; Parker, Martin J.

doi:10.1016/j.jmb.2004.08.105

Cited by 28 publications

(20 citation statements)

References 42 publications

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“…Using constraints derived from NMR, we modeled the structure of the complex between PrP and Fe(III)-TMPyP. The initial model, produced using the NMR intensity data displayed on the PrP backbone, was refined using in-house docking software (BUDE) (37)(38)(39).…”

Section: Resultsmentioning

confidence: 99%

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Pharmacological chaperone for the structured domain of human prion protein

Nicoll¹,

Trevitt

Tattum

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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In prion diseases, the misfolded protein aggregates are derived from cellular prion protein (PrP C ). Numerous ligands have been reported to bind to human PrP C (huPrP), but none to the structured region with the affinity required for a pharmacological chaperone. Using equilibrium dialysis, we screened molecules previously suggested to interact with PrP to discriminate between those which did not interact with PrP, behaved as nonspecific polyionic aggregates or formed a genuine interaction. Those that bind could potentially act as pharmacological chaperones. Here we report that a cationic tetrapyrrole [Fe(III)-TMPyP], which displays potent antiprion activity, binds to the structured region of huPrP. Using a battery of biophysical techniques, we demonstrate that Fe(III)-TMPyP forms a 1∶1 complex via the structured C terminus of huPrP with a K d of 4.5 ± 2 μM, which is in the range of its IC 50 for curing prion-infected cells of 1.6 ± 0.4 μM and the concentration required to inhibit protein-misfolding cyclic amplification. Therefore, this molecule tests the hypothesis that stabilization of huPrP C , as a principle, could be used in the treatment of human prion disease. The identification of a binding site with a defined 3D structure opens up the possibility of designing small molecules that stabilize huPrP and prevent its conversion into the disease-associated form.

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Section: Resultsmentioning

confidence: 99%

“…The NMR structure (1QLX) of residues 23-230 of the human prion protein was used for modeling the interaction between PrP c and Fe(III)-TMPyP. The initial model was refined using in-house docking software (37)(38)(39).…”

Section: Methodsmentioning

confidence: 99%

Pharmacological chaperone for the structured domain of human prion protein

Nicoll¹,

Trevitt

Tattum

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The effect of the solvation/desolvation barriers in protein folding is most obvious when comparing simulations with and without the explicit inclusion of the barriers in the potential energy function. Incorporation of solvation/desolvation barriers in folding simulations based on a semi-realistic off-lattice protein model for several peptides with well defined native states, results in an increase of the average energy for the non-native states, increased stability of the native state and an increase in folding cooperativity, relative to the same simulations in the absence of the desolvation barriers [65]. In all cases, the folding rate is increased when the desolvation barriers are included.…”

Section: Water Affects the Energy Landscapementioning

confidence: 92%

“…Within the context of a protein, the nature of these local transition barriers can vary depending on the groups near the interacting atoms in such a way to favor some conformations over others (see Figure 4 for a comparison of the solvation/desolvation barriers for two approaching methane molecules versus alanine molecules). In this manner, solvation/desolvation barriers collectively can have a profound effect on the rate-limiting step in protein folding [64], affecting the energy landscape as to minimize frustration [65]. The effect of the solvation/desolvation barriers in protein folding is most obvious when comparing simulations with and without the explicit inclusion of the barriers in the potential energy function.…”

Section: Water Affects the Energy Landscapementioning

confidence: 99%

Minimizing frustration by folding in an aqueous environment

Mattos

Clark

2008

Archives of Biochemistry and Biophysics

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Although life as we know it evolved in an aqueous medium, the properties of water are not completely understood. In this review, we focus on the role of water in guiding protein folding and stability. Specifically, we discuss the mechanisms of protein folding in an aqueous environment, the effects of water on the folding energy landscape as well as the transition state ensemble, and interactions of water with the folded state. We show that water cannot be viewed as a passive solvent, but rather, plays a very active role in the life of a protein.

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“…31,32 We have been developing a coarse-grained model for simulating polypeptides called RAFT (reduced Ramachandran angle and folding force field for tertiary structure prediction). [33][34][35][36] RAFT uses idealized covalent bonds, discrete backbone torsion angles, fixed side chains, and unified atoms; and employs a semiempirical physicochemical force field (implicit solvent) involving pairwise potentials of mean force describing steric, hydrophobic, H-bonding, and ionion interactions derived from experimental data. Discrete models like RAFT lend themselves well to Monte Carlo (MC) sampling methods for estimating Boltzmann averaged properties.…”

Section: Introductionmentioning

confidence: 99%

Identification of amyloidogenic peptide sequences using a coarse‐grained physicochemical model

Clarke

Parker

2008

J Comput Chem

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Cross-beta amyloid is implicated in over 20 human diseases. Experiments suggest that specific sequence elements within amyloidogenic proteins play a major role in seeding amyloid formation. Identifying these seeding sequences is important for rationalizing the molecular mechanisms of amyloid formation and for elaborating therapeutic strategies that target amyloid. Theoretical techniques play an important role in facilitating the identification and structural characterization of putative seeding sequences; most amyloid species are not amenable to high resolution experimental structure techniques. In this study we have combined a coarse-grained physicochemical protein model with a highly efficient Monte Carlo sampling technique to identify amyloidogenic sequences in four proteins for which respective experimental peptide fragmentation data exist. Peptide sequences were defined as amyloidogenic if the ensemble structure predicted for three interacting peptides described a stable and regular three-stranded beta-sheet. For such peptides, free energies were calculated to provide a measure of amyloid propensity. The overall agreement between the experimental and predicted data is good, and we correctly identify several self-recognition motifs proposed to define the cross-beta amyloid fibril architectures of two of the proteins. Our results compare very favorably with those obtained using atomistic molecular dynamics methods, though our simulations are 30-40 times faster.

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Water as a Conformational Editor in Protein Folding

Cited by 28 publications

References 42 publications

Pharmacological chaperone for the structured domain of human prion protein

Pharmacological chaperone for the structured domain of human prion protein

Minimizing frustration by folding in an aqueous environment

Identification of amyloidogenic peptide sequences using a coarse‐grained physicochemical model

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