Search

Your search keyword '"Daggett, Valerie"' showing total 853 results
Start Over Author "Daggett, Valerie"

Refine your results

more »

more »

more »

more »
853 results on '"Daggett, Valerie"'

151. Staphylococcal protein A: Unfolding pathways, unfolded states, and differences between the B and E domains

Author

Alonso, Darwin O. V. and Daggett, Valerie

Subjects
Staphylococcus -- Research, Proteins -- Research, Science and technology
Abstract

We present multiple native and denaturation simulations of the B and E domains of the three-helix bundle protein A, totaling 60 ns. The C-terminal helix (H3) consistently denatures later than either of the other two helices and contains residual helical structure in the denatured state. These results are consistent with experiments suggesting that the isolated H3 fragment is more stable than H1 and H2 and that H3 forms early in folding. Interestingly, the denatured state of the B domain is much more compact than that of the E domain. This sequence-dependent effect on the dimensions of the denatured state and the lack of correlation with structure suggest that the radius of gyration can be a misleading reaction coordinate for unfolding/folding. Various unfolding and refolding events are observed in the denaturation simulations. In some cases, the transitions are facilitated through interactions with other portions of the protein--contact-assisted helix formation. In the native simulations, the E domain is very stable: after 6 ns, the [C.sup.[Alpha]] root-mean-square deviation from the starting structure is less than 1.4 [Angstrom]. In contrast, the native state of the B domain deviates more and its inter-helical angles fluctuate. In apparent contrast, we note that the B domain is thermodynamically more stable than the E domain. The simulations suggest that the increased stability of the B domain may be due to heightened mobility, and therefore entropy, in the native state and decreased mobility/entropy in the more compact denatured state.

Published
2000

152. Dynameomics: Data-driven methods and models for utilizing large-scale protein structure repositories for improving fragment-based loop prediction

Author

Rysavy, Steven J, Beck, David AC, and Daggett, Valerie

Subjects
Protein Conformation, Sequence Analysis, Protein, Computational Biology, Proteins, Articles, Molecular Dynamics Simulation, Databases, Protein
Abstract

Protein function is intimately linked to protein structure and dynamics yet experimentally determined structures frequently omit regions within a protein due to indeterminate data, which is often due protein dynamics. We propose that atomistic molecular dynamics simulations provide a diverse sampling of biologically relevant structures for these missing segments (and beyond) to improve structural modeling and structure prediction. Here we make use of the Dynameomics data warehouse, which contains simulations of representatives of essentially all known protein folds. We developed novel computational methods to efficiently identify, rank and retrieve small peptide structures, or fragments, from this database. We also created a novel data model to analyze and compare large repositories of structural data, such as contained within the Protein Data Bank and the Dynameomics data warehouse. Our evaluation compares these structural repositories for improving loop predictions and analyzes the utility of our methods and models. Using a standard set of loop structures, containing 510 loops, 30 for each loop length from 4 to 20 residues, we find that the inclusion of Dynameomics structures in fragment-based methods improves the quality of the loop predictions without being dependent on sequence homology. Depending on loop length, ∼ 25-75% of the best predictions came from the Dynameomics set, resulting in lower main chain root-mean-square deviations for all fragment lengths using the combined fragment library. We also provide specific cases where Dynameomics fragments provide better predictions for NMR loop structures than fragments from crystal structures. Online access to these fragment libraries is available at http://www.dynameomics.org/fragments.

Published
2014

160. Molecular dynamics as an approach to study prion protein misfolding and the effect of pathogenic mutations

Author

van der Kamp, Marc W and Daggett, Valerie

Subjects
Models, Molecular, Protein Denaturation, Protein Folding, Magnetic Resonance Spectroscopy, Prions, Protein Conformation, Hydrogen-Ion Concentration, Molecular Dynamics Simulation, Protein Structure, Secondary, Recombinant Proteins, Prion Diseases, Mutation, Animals, Humans, Software
Abstract

Computer simulation of protein dynamics offers unique high-resolution information that complements experiment. Using experimentally derived structures of the natively folded prion protein (PrP), physically realistic dynamics and conformational changes can be simulated, including the initial steps of misfolding. By introducing mutations in silico, the effect of pathogenic mutations on PrP conformation and dynamics can be assessed. Here, we briefly introduce molecular dynamics methods and review the application of molecular dynamics simulations to obtain insight into various aspects of the PrP, including the mechanism of misfolding, the response to changes in the environment, and the influence of disease-related mutations.

Published
2011

161. The dynameomics rotamer library: Amino acid side chain conformations and dynamics from comprehensive molecular dynamics simulations in water

Author

Scouras, Alexander D and Daggett, Valerie

Subjects
Protein Folding, Proteins, Water, Amino Acid Sequence, Amino Acids, Molecular Dynamics Simulation, Article, Protein Structure, Tertiary
Abstract

We have recently completed systematic molecular dynamics simulations of 807 different proteins representing 95% of the known autonomous protein folds in an effort we refer to as Dynameomics. Here we focus on the analysis of side chain conformations and dynamics to create a dynamic rotamer library. Overall this library is derived from 31,000 occurrences of each of 86,217 different residues, or 2.7 × 10(9) rotamers. This dynamic library has 74% overlap of rotamer distributions with rotamer libraries derived from static high-resolution crystal structures. Seventy-five percent of the residues had an assignable primary conformation, and 68% of the residues had at least one significant alternate conformation. The average correlation time for switching between rotamers ranged from 22 ps for Met to over 8 ns for Cys; this time decreased 20-fold on the surface of the protein and modestly for dihedral angles further from the main chain. Side chain S(2) axis order parameters were calculated and they correlated well with those derived from NMR relaxation experiments (R = 0.9). Relationships relating the S(2) axis order parameters to rotamer occupancy were derived. Overall the Dynameomics rotamer library offers a comprehensive depiction of side chain rotamer preferences and dynamics in solution, and more realistic distributions for dynamic proteins in solution at ambient temperature than libraries derived from crystal structures, in particular charged surface residues are better represented. Details of the rotamer library are presented here and the library itself can be downloaded at http://www.dynameomics.org.

Published
2010

162. Structural and functional diversity among amyloid proteins: Agents of disease, building blocks of biology, and implications for molecular engineering.

Author

Bleem, Alissa and Daggett, Valerie

Abstract

ABSTRACT Amyloids have long been associated with protein dysfunction and neurodegenerative diseases, but recent research has demonstrated that some organisms utilize the unique properties of the amyloid fold to create functional structures with important roles in biological processes. Additionally, new engineering approaches have taken advantage of amyloid structures for implementation in a wide variety of materials and devices. In this review, the role of amyloid in human disease is discussed and compared to the functional amyloids, which serve a largely structural purpose. We then consider the use of amyloid constructs in engineering applications, including their utility as building blocks for synthetic biology and molecular engineering. Biotechnol. Bioeng. 2017;114: 7-20. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
View/download PDF

170. Chemical and Physical Variability in Structural Isomers of an l/dα-Sheet Peptide Designed To Inhibit Amyloidogenesis

Author

Maris, Nathan L., Shea, Dylan, Bleem, Alissa, Bryers, James D., and Daggett, Valerie

Abstract

There has been much interest in synthetic peptides as inhibitors of aggregation associated with amyloid diseases. Of particular interest are compounds that target the cytotoxic soluble oligomers preceding the formation of mature, nontoxic fibrils. This study explores physical and chemical differences between two de novo-designed peptides that share an identical primary structure but differ in backbone chirality at six key positions. We show that the presence of alternating l/d-amino acid motifs dramatically increases aqueous solubility, enforces α-sheet secondary structure, and inhibits aggregation of the β-amyloid peptide implicated in Alzheimer’s disease, in addition to neutralizing its cytotoxicity. In contrast, the all-l-amino acid isomer does not form α-sheet structure and is insoluble and inactive.

Published
2017
Full Text
View/download PDF

172. Altering diffusivity in biological solutions through modification of solution structure and dynamics

Author

Laidig, Keith E., Gainer, John L., and Daggett, Valerie

Subjects
Oxygen -- Diffusion rate, Sodium compounds -- Research, Chemical reactions -- Analysis, Diffusion -- Analysis, Chemistry
Abstract

The atomic interactions resulting from the addition of trans-sodium crocetinate (TSC) were analyzed to explain the diffusion of oxygen through aqueous solutions. The diffusivity levels of oxygen which were recorded at 3-5 Angstrom from TSC within the shell were larger than the bulk value. Moreover, hydrophobic hydration established an orderly channel which facilitated the efficient diffusion of oxygen in aqueous solutions.

Published
1998

178. An in silico algorithm for identifying stabilizing pockets in proteins: test case, the Y220C mutant of the p53 tumor suppressor protein.

Author

Bromley, Dennis, Bauer, Matthias R., Fersht, Alan R., and Daggett, Valerie

Subjects
P53 protein, APOPTOSIS, CELL cycle, GENETIC mutation, CANCER risk factors
Abstract

The p53 tumor suppressor protein performs a critical role in stimulating apoptosis and cell cycle arrest in response to oncogenic stress. The function of p53 can be compromised by mutation, leading to increased risk of cancer; approximately 50% of cancers are associated with mutations in the p53 gene, the majority of which are in the core DNA-binding domain. The Y220C mutation of p53, for example, destabilizes the core domain by 4 kcal/mol, leading to rapid denaturation and aggregation. The associated loss of tumor suppressor functionality is associated with approximately 75 000 new cancer cases every year. Destabilized p53 mutants can be 'rescued' and their function restored; binding of a small molecule into a pocket on the surface of mutant p53 can stabilize its wild-type structure and restore its function. Here, we describe an in silico algorithm for identifying potential rescue pockets, including the algorithm's integration with the Dynameomics molecular dynamics data warehouse and the DIVE visual analytics engine. We discuss the results of the application of the method to the Y220C p53 mutant, entailing finding a putative rescue pocket through MD simulations followed by an in silico search for stabilizing ligands that dock into the putative rescue pocket. The top three compounds from this search were tested experimentally and one of them bound in the pocket, as shown by nuclear magnetic resonance, and weakly stabilized the mutant. [ABSTRACT FROM AUTHOR]

Published
2016
Full Text
View/download PDF

198. Dynameomics: A Comprehensive Database of Protein Dynamics

Author

van der Kamp, Marc W., primary, Schaeffer, R. Dustin, additional, Jonsson, Amanda L., additional, Scouras, Alexander D., additional, Simms, Andrew M., additional, Toofanny, Rudesh D., additional, Benson, Noah C., additional, Anderson, Peter C., additional, Merkley, Eric D., additional, Rysavy, Steven, additional, Bromley, Dennis, additional, Beck, David A.C., additional, and Daggett, Valerie, additional

Published
2010
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results