Ab initio protein structure prediction using physicochemical potentials and a simplified off-lattice model

Gibbs, N; Clarke, Anthony R.; Sessions, Richard B.

doi:10.1002/1097-0134(20010501)43:2<186::aid-prot1030>3.0.co;2-l

Cited by 49 publications

(40 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

See 1 more Smart Citation

Pharmacological chaperone for the structured domain of human prion protein

Nicoll¹,

Trevitt

Tattum

et al. 2010

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Enzyme-The possible conformations available to the unrestrained N-terminal extension of L1 (as would be likely to exist in the monomer) were computed using the ab-initio evolutionary Monte Carlo technique of Gibbs et al (40). For the first 19 N-terminal amino acids, an initial set of structures was generated with backbone -geometries applied randomly.…”

Section: Modeling Of the N-terminal Extension In The Monomermentioning

confidence: 99%

Characterization of Monomeric L1 Metallo-β-lactamase and the Role of the N-terminal Extension in Negative Cooperativity and Antibiotic Hydrolysis

Simm¹,

Higgins²,

Carenbauer³

et al. 2002

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The L1 metallo-␤-lactamase from Stenotrophomonas maltophilia is unique among this class of enzymes because it is tetrameric. Previous work predicted that the two regions of important intersubunit interaction were the residue Met-140 and the N-terminal extensions of each subunit. The N-terminal extension was also implicated in ␤-lactam binding. Mutation of methionine 140 to aspartic acid results in a monomeric L1 ␤-lactamase with a greatly altered substrate specificity profile. A 20-amino acid N-terminal deletion mutant enzyme (NDel) could be isolated in a tetrameric form but demonstrated greatly reduced rates of ␤-lactam hydrolysis and different substrate profiles compared with that of the parent enzyme. Specific site-directed mutations of individual N terminus residues were made (Y11S, W17S, and a double mutant L5A/L8A). All N-terminal mutant enzymes were tetramers and all showed higher K m values for ampicillin and nitrocefin, hydrolyzed ceftazidime poorly, and hydrolyzed imipenem more efficiently than ampicillin in contrast to wild-type L1. Nitrocefin turnover was significantly increased, probably because of an increased rate of breakdown of the intermediate species due to a lack of stabilizing forces. K m values for monomeric L1 were greatly increased for all antibiotics tested. A model of a highly mobile N-terminal extension in the monomeric enzyme is proposed to explain these findings. Tetrameric L1 shows negative cooperativity, which is not present in either the monomer or N-terminal deletion enzymes, suggesting that the cooperative effect is mediated via N-terminal intersubunit interactions. These data indicate that while the N terminus of L1 is not essential for ␤-lactam hydrolysis, it is clearly important to its activity and substrate specificity.

show abstract

“…For very simple discrete models, all conformations could be enumerated [20,76,96,141,[255][256][257][258][259][260] and an exact analysis of the model thermodynamics performed [20,261]. Structure and thermodynamics of more complex models are studied via classical molecular dynamics [262 -267] (MD), Monte Carlo (MC) methods [26,109,129,158 -160,167,168, 237,239,268-274], genetic algorithms and hybrid combinations of these methods [275]. The dynamics of continuous reduced models could be studied via classical MD [36,201, 204,265 -267,276,277] or its variants [263] (for instance, Brownian dynamics [265,278]), but also via various MC schemes [209,210] or combinations of various methods of global minimization [275].…”

Section: Sampling Conformational Space Of Reduced Modelsmentioning

confidence: 99%

“…Structure and thermodynamics of more complex models are studied via classical molecular dynamics [262 -267] (MD), Monte Carlo (MC) methods [26,109,129,158 -160,167,168, 237,239,268-274], genetic algorithms and hybrid combinations of these methods [275]. The dynamics of continuous reduced models could be studied via classical MD [36,201, 204,265 -267,276,277] or its variants [263] (for instance, Brownian dynamics [265,278]), but also via various MC schemes [209,210] or combinations of various methods of global minimization [275]. Long time dynamics of discrete models could be studied using Monte Carlo dynamics (MCD) schemes [22,60,69,146,163,166,[172][173][174][175]233,268,279].…”

Section: Sampling Conformational Space Of Reduced Modelsmentioning

confidence: 99%

Reduced models of proteins and their applications

Koliński

Skolnick

2004

Polymer

174

143

View full text Add to dashboard Cite

Reduced computer modeling of proteins now has a history of about 30 years. In spite of the enormous increase in computing abilities, reduced models are still very important tools for theoretical studies of protein structure, dynamics and thermodynamics. Very simple, highly idealized lattice (and recently also off-lattice) models could be studied in great detail, providing valuable insight into the most general factors governing structure stability, folding kinetics and interactions responsible for characteristic two-state behavior near the folding temperature. More complex models now enable modeling of real proteins on the level of low to moderate resolution, allowing us to address more detailed questions. Ab initio protein structure predictions, still being far from a routine task, have become feasible. When supported by evolutionary information from multiple sequence alignments and potential local and/or global structural similarity to known structures, reduced modeling opens up new areas of comparative modeling, thereby complementing contemporary structural genomics. q

show abstract

Ab initio protein structure prediction using physicochemical potentials and a simplified off-lattice model

Cited by 49 publications

References 42 publications

Pharmacological chaperone for the structured domain of human prion protein

Pharmacological chaperone for the structured domain of human prion protein

Characterization of Monomeric L1 Metallo-β-lactamase and the Role of the N-terminal Extension in Negative Cooperativity and Antibiotic Hydrolysis

Reduced models of proteins and their applications

Contact Info

Product

Resources

About