Density guided importance sampling: application to a reduced model of protein folding

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

doi:10.1093/bioinformatics/bti421

Cited by 8 publications

(15 citation statements)

References 27 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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“…This report does not cover the geometry optimization including equilibrium and transition structures, Henkelman et al 2000a;Olsen et al 2004;Schlegel 1982Schlegel , 2003Schlegel , 2011 conformational sampling, (Beusen 1996;Leach 1991;Parish 2002) or global minimum search methodologies, (Floudas & Pardalos 1996;Horst 1995Horst , 2000Torn 1989) which are all important for the studies of computational chemistry and biology. Other related topics, including enhanced sampling methods, (Earl & Deem 2005;Hamelberg et al 2004;Lei & Duan 2007;Okur et al 2006;Sugita 1999;Swendsen & Wang 1986;Thomas et al 2005;Wen et al 2004) simulation of nonequilibrium states, (Bair et al 2002;Cummings & Evans 1992;Hoover 1983;Hoover & Hoover 2005;Kjelstrup & Hafskjold 1996;Li et al 2008;Mundy et al 2000) and minimization methods, (Bonnans 2003;Dennis & Schnabel 1996;Fletcher 2000;Gill 1982;Haslinger & Mäkinen 2003;Nocedal 2006;Scales 1985) are not covered in this chapter either. The curious readers are welcome to read cited references for more information.…”

Section: Introductionmentioning

confidence: 99%

Reaction Path Optimization and Sampling Methods and Their Applications for Rare Events

Tao¹,

Larkin²,

Brooks³

2012

Some Applications of Quantum Mechanics

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“…Alongside RAFT we have developed a hybrid MC method called density-guided importance sampling (DGIS). 35 This combines the best features of temperature-dependent 37 and -independent 38 MC methods. DGIS is both fast and accurate, outperforming other hybrid MC methods designed to optimize sampling rates, notably the widely used replica exchange method.…”

Section: Introductionmentioning

confidence: 99%

“…DGIS is both fast and accurate, outperforming other hybrid MC methods designed to optimize sampling rates, notably the widely used replica exchange method. 35 Good predictions for a comprehensive set of a-helical and b-hairpin peptides were made using RAFT and DGIS recently. 36 In the same study, ensemble structures were predicted for 12 peptides known to form cross-b amyloid fibrils.…”

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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Density guided importance sampling: application to a reduced model of protein folding

Abstract: m.j.parker@leeds.ac.uk.

Cited by 8 publications

References 27 publications

Pharmacological chaperone for the structured domain of human prion protein

Pharmacological chaperone for the structured domain of human prion protein

Reaction Path Optimization and Sampling Methods and Their Applications for Rare Events

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

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