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Protein Loop Dynamics Are Complex And Depend On The Motions Of The Whole Protein, Michael T. Zimmermann, Robert L. Jernigan 2017 Iowa State University

Protein Loop Dynamics Are Complex And Depend On The Motions Of The Whole Protein, Michael T. Zimmermann, Robert L. Jernigan

Robert Jernigan

We investigate the relationship between the motions of the same peptide loop segment incorporated within a protein structure and motions of free or end-constrained peptides. As a reference point we also compare against alanine chains having the same length as the loop. Both the analysis of atomic molecular dynamics trajectories and structure-based elastic network models, reveal no general dependence on loop length or on the number of solvent exposed residues. Rather, the whole structure affects the motions in complex ways that depend strongly and specifically on the tertiary structure of the whole protein. Both the Elastic Network Models and Molecular ...


Factors Correlating With Significant Differences Between X-Ray Structures Of Myoglobin, Alexander A. Rashin, Marcin J. Domagalski, Michael T. Zimmermann, Wladek Minor, Maksymilian Chruszcz, Robert L. Jernigan 2017 BioChemComp Inc

Factors Correlating With Significant Differences Between X-Ray Structures Of Myoglobin, Alexander A. Rashin, Marcin J. Domagalski, Michael T. Zimmermann, Wladek Minor, Maksymilian Chruszcz, Robert L. Jernigan

Robert Jernigan

Validation of general ideas about the origins of conformational differences in proteins is critical in order to arrive at meaningful functional insights. Here, principal component analysis (PCA) and distance difference matrices are used to validate some such ideas about the conformational differences between 291 myoglobin structures from sperm whale, horse and pig. Almost all of the horse and pig structures form compact PCA clusters with only minor coordinate differences and outliers that are easily explained. The 222 whale structures form a few dense clusters with multiple outliers. A few whale outliers with a prominent distortion of the GH loop are ...


Protein Flexibility: Coordinate Uncertainties And Interpretation Of Structural Differences, Alexander A. Rashin, Abraham H. L. Rashin, Robert L. Jernigan 2017 BioChemComp Inc

Protein Flexibility: Coordinate Uncertainties And Interpretation Of Structural Differences, Alexander A. Rashin, Abraham H. L. Rashin, Robert L. Jernigan

Robert Jernigan

Valid interpretations of conformational movements in protein structures determined by X-ray crystallography require that the movement magnitudes exceed their uncertainty threshold. Here, it is shown that such thresholds can be obtained from the distance difference matrices (DDMs) of 1014 pairs of independently determined structures of bovine ribonuclease A and sperm whale myoglobin, with no explanations provided for reportedly minor coordinate differences. The smallest magnitudes of reportedly functional motions are just above these thresholds. Uncertainty thresholds can provide objective criteria that distinguish between true conformational changes and apparent `noise', showing that some previous interpretations of protein coordinate changes attributed to external ...


Phylogenetic Evidence From Freshwater Crayfishes That Cave Adaptation Is Not An Evolutionary Dead-End., David B Stern, Jesse Breinholt, Carlos Pedraza-Lara, Marilú López-Mejía, Christopher L Owen, Heather Bracken-Grissom, James W Fetzner, Keith A Crandall 2017 George Washington University

Phylogenetic Evidence From Freshwater Crayfishes That Cave Adaptation Is Not An Evolutionary Dead-End., David B Stern, Jesse Breinholt, Carlos Pedraza-Lara, Marilú López-Mejía, Christopher L Owen, Heather Bracken-Grissom, James W Fetzner, Keith A Crandall

Computational Biology Institute

Caves are perceived as isolated, extreme habitats with a uniquely specialized biota, which long ago led to the idea that caves are "evolutionary dead-ends." This implies that cave-adapted taxa may be doomed for extinction before they can diversify or transition to a more stable state. However, this hypothesis has not been explicitly tested in a phylogenetic framework with multiple independently evolved cave-dwelling groups. Here, we use the freshwater crayfish, a group with dozens of cave-dwelling species in multiple lineages, as a system to test this hypothesis. We consider historical patterns of lineage diversification and habitat transition as well as current ...


A Combined Computational Strategy Of Sequence And Structural Analysis Predicts The Existence Of A Functional Eicosanoid Pathway In Drosophila Melanogaster, Michael Scarpati 2017 The Graduate Center, City University of New York

A Combined Computational Strategy Of Sequence And Structural Analysis Predicts The Existence Of A Functional Eicosanoid Pathway In Drosophila Melanogaster, Michael Scarpati

All Graduate Works by Year: Dissertations, Theses, and Capstone Projects

With increased understanding of their roles in signal transduction and metabolism, eicosanoids have emerged as important players in human health and disease. Mammalian prostanoids and related lipid mediators perform varied functions in different tissues and organs. Synthesized through the oxygenation of C20 polyunsaturated fatty acids, mammalian eicosanoids are both pro- and anti-inflammatory. The physiological contexts in which eicosanoid family members act at the cellular level are not well understood. In this study, we examined whether the genome of Drosophila melanogaster, a powerful model for innate immunity and inflammation, codes for the enzymes required for eicosanoid biosynthesis. We report the existence ...


Determining The Structure Of Phospholipase C Epsilon, Hannah O'Neill, Monita Sieng, Elisabeth Garland-Kuntz, Angeline Lyon 2017 Purdue University

Determining The Structure Of Phospholipase C Epsilon, Hannah O'Neill, Monita Sieng, Elisabeth Garland-Kuntz, Angeline Lyon

The Summer Undergraduate Research Fellowship (SURF) Symposium

The phospholipase C (PLC) epsilon subfamily of PLC enzymes are found at highest concentration within the cardiovascular system. Improper functioning of the enzyme, whether due to overstimulation or changes in expression, has far-reaching effects within the human body Stunted heart valve development and cardiac hypertrophy and are two such examples. The mechanisms by which PLC epsilon activity is regulated in these processes remain unknown, as does the physical structure of the enzyme. In this study, we seek to determine the structure of a PLC epsilon fragment that retains enzymatic activity and is amenable to crystallization. Mutagenesis of PLC epsilon cDNA ...


Crystal Structure Of Apobec3a Bound To Single-Stranded Dna Reveals Structural Basis For Cytidine Deamination And Specificity, Takahide Kouno, Tania V. Silvas, Brendan J. Hilbert, Shivender Shandilya, Markus-Frederik Bohn, Brian A. Kelch, William E. Royer, Mohan Somasundaran, Nese Kurt Yilmaz, Hiroshi Matsuo, Celia A. Schiffer 2017 University of Massachusetts Medical School

Crystal Structure Of Apobec3a Bound To Single-Stranded Dna Reveals Structural Basis For Cytidine Deamination And Specificity, Takahide Kouno, Tania V. Silvas, Brendan J. Hilbert, Shivender Shandilya, Markus-Frederik Bohn, Brian A. Kelch, William E. Royer, Mohan Somasundaran, Nese Kurt Yilmaz, Hiroshi Matsuo, Celia A. Schiffer

Celia A. Schiffer

Nucleic acid editing enzymes are essential components of the immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins, and contribute to the diversification and lethality of cancers. Among these enzymes are the seven human APOBEC3 deoxycytidine deaminases, each with unique target sequence specificity and subcellular localization. While the enzymology and biological consequences have been extensively studied, the mechanism by which APOBEC3s recognize and edit DNA remains elusive. Here we present the crystal structure of a complex of a cytidine deaminase with ssDNA bound in the active site at 2.2 A. This structure not only visualizes the active ...


Molecular Mechanisms Of C-Terminal Eps15 Homology Domain Containing (Ehd) Protein Function, Kriti Bahl 2017 University of Nebraska Medical Center

Molecular Mechanisms Of C-Terminal Eps15 Homology Domain Containing (Ehd) Protein Function, Kriti Bahl

Theses & Dissertations

Endocytic trafficking is not only an essential process for the maintenance of cellular homeostasis but also plays a vital role in regulating diverse cellular processes such as signaling, migration and cell division. The C-terminal Eps 15 Homology Domain proteins (EHD1-4) play pivotal roles in regulating distinct steps of endocytic trafficking. Among the EHDs, EHD2 is disparate both in terms of sequence homology (70%) and its subcellular localization at the caveolae. The crystal structure of EHD2 has been solved and it contains an unstructured loop consisting of two proline-phenylalanine (PF) motifs: KPFRKLNPF. However, the other paralogs EHD1, EHD3 ...


Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer 2017 University of Massachusetts Medical School

Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a ...


Transcriptomic Differentiation Underlying Marine‐To‐Freshwater Transitions In The South American Silversides Odontesthes Argentinensis And O. Bonariensis (Atheriniformes), Lily Hughes, Gustavo Somoza, Bryan Nguyen, James Bernot, Mariano Gonzalez-Castro, Juan Martin Diaz de Astarloa, Guillermo Orti 2017 George Washington University

Transcriptomic Differentiation Underlying Marine‐To‐Freshwater Transitions In The South American Silversides Odontesthes Argentinensis And O. Bonariensis (Atheriniformes), Lily Hughes, Gustavo Somoza, Bryan Nguyen, James Bernot, Mariano Gonzalez-Castro, Juan Martin Diaz De Astarloa, Guillermo Orti

Computational Biology Institute

Salinity gradients are critical habitat determinants for freshwater organisms. Silverside fishes in the genus Odontesthes have recently and repeatedly transitioned from marine to freshwater habitats, overcoming a strong ecological barrier. Genomic and transcriptomic changes involved in this kind of transition are only known for a few model species. We present new data and analyses of gene expression and microbiome composition in the gills of two closely related silverside species, marine O. argentinensis and freshwater O. bonariensis and find more than three thousand transcripts differentially expressed, with osmoregulatory/ion transport genes and immune genes showing very different expression patterns across species ...


Efficient Heterocyclisation By (Di)Terpene Synthases, S. Mafu, K. C. Potter, M. L. Hillwig, S. Schulte, J. Criswell, R. J. Peters 2017 Iowa State University

Efficient Heterocyclisation By (Di)Terpene Synthases, S. Mafu, K. C. Potter, M. L. Hillwig, S. Schulte, J. Criswell, R. J. Peters

Reuben J. Peters

While cyclic ether forming terpene synthases are known, the basis for such heterocyclisation is unclear. Here it is reported that numerous (di)terpene synthases, particularly including the ancestral ent-kaurene synthase, efficiently produce isomers of manoyl oxide from the stereochemically appropriate substrate. Accordingly, such heterocyclisation is easily accomplished by terpene synthases. Indeed, the use of single residue changes to induce production of the appropriate substrate in the upstream active site leads to efficient bifunctional enzymes producing isomers of manoyl oxide, representing novel enzymatic activity.


Blocking Deprotonation With Retention Of Aromaticity In A Plant Ent-Copalyl Diphosphate Synthase Leads To Product Rearrangement, Kevin C. Potter, Jiachen Zi, Young J. Hong, Samuel Schulte, Brandi Malchow, Dean J. Tantillo, Reuben J. Peters 2017 Iowa State University

Blocking Deprotonation With Retention Of Aromaticity In A Plant Ent-Copalyl Diphosphate Synthase Leads To Product Rearrangement, Kevin C. Potter, Jiachen Zi, Young J. Hong, Samuel Schulte, Brandi Malchow, Dean J. Tantillo, Reuben J. Peters

Reuben J. Peters

Biosynthesis of the labdane-related diterpenoids, a large superfamily of over 7,000 natural products, is characterized by the use of class II diterpene cyclases.[1] The vast majority of these biocatalysts are exclusively found in plants, stemming from repeated evolutionary diversification of the ent-copalyl diphosphate synthase (CPS) required for gibberellin phytohormone biosynthesis – i.e., via gene duplication and neofunctionalization.[2] As implied by this evolutionary scenario, these enzymes must exhibit catalytic plasticity that enables new products to readily arise. Consistent with this hypothesis, we have shown that substitution of smaller residues for the catalytic base group can lead to the ...


A Single Residue Switch Converts Abietadiene Synthase Into A Pimaradiene Specific Cyclase, P. Ross Wilderman, Reuben J. Peters 2017 Iowa State University

A Single Residue Switch Converts Abietadiene Synthase Into A Pimaradiene Specific Cyclase, P. Ross Wilderman, Reuben J. Peters

Reuben J. Peters

Terpene synthases often catalyze complex cyclization reactions that typically represent the committed step in particular biosynthetic pathways, leading to great interest in their enzymatic mechanisms. We have recently demonstrated that substitution of a specific Ile with Thr was sufficient to “short circuit” the complex cyclization reaction normally catalyzed by ent-kaurene synthases to instead produce ent-pimaradiene. Here we report that the complex cyclization/rearrangement reaction catalyzed by abietadiene synthase can be similarly cut short to produce pimaradienes by an analogous Ser for Ala change, albeit with a slight shift in active site location to accommodate the difference in substrate ...


Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer 2017 University of Massachusetts Medical School

Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency ...


Two Rings In Them All: The Labdane-Related Diterpenoids, Reuben J. Peters 2017 Iowa State University

Two Rings In Them All: The Labdane-Related Diterpenoids, Reuben J. Peters

Reuben J. Peters

In his original exposition of the biogenetic isoprenoid rule, L. Ruzicka noted the structural identity between the fused A/B rings of triterpenoids/sterols and certain multicyclic diterpenoids as part of the impetus leading to that profound insight. His prescient hypothesis that this chemical structure relationship reflects similarities in the initial cyclization of these diterpenoids with that occurring in triterpenoid biosynthesis has since been verified. However, this chemical structure relationship does not continue to hold true for the additional rings found in many of these di- and tri- terpenoid natural products. This is now appreciated to arise from differences in ...


Terpenoid Synthase Structures: A So Far Incomplete View Of Complex Catalysis, Yang Gao, Richard B. Honzatko, Reuben J. Peters 2017 Iowa State University

Terpenoid Synthase Structures: A So Far Incomplete View Of Complex Catalysis, Yang Gao, Richard B. Honzatko, Reuben J. Peters

Reuben J. Peters

The complexity of terpenoid natural products has drawn significant interest, particularly since their common (poly)isoprenyl origins were discovered. Notably, much of this complexity is derived from the highly variable cyclized and/or rearranged nature of the observed hydrocarbon skeletal structures. Indeed, at least in some cases it is difficult to immediately recognize their derivation from poly-isoprenyl precursors. Nevertheless, these diverse structures are formed by sequential elongation to acyclic precursors, most often with subsequent cyclization and/or rearrangement. Strikingly, the reactions used to assemble and diversify terpenoid backbones share a common carbocationic driven mechanism, although the means by which the ...


Rnaseq Analysis Of The Drosophila Response To The Entomopathogenic Nematode Steinernema., Shruti Yadav, Sean Daugherty, Amol Carl Shetty, Ioannis Eleftherianos 2017 George Washington University

Rnaseq Analysis Of The Drosophila Response To The Entomopathogenic Nematode Steinernema., Shruti Yadav, Sean Daugherty, Amol Carl Shetty, Ioannis Eleftherianos

Computational Biology Institute

Drosophila melanogaster is an outstanding model to study the molecular and functional basis of host-pathogen interactions. Currently, our knowledge of microbial infections in D. melanogaster is well understood; however, the response of flies to nematode infections is still in its infancy. Here, we have used the potent parasitic nematode Steinernema carpocapsae, which lives in mutualism with its endosymbiotic bacteria Xenorhabdus nematophila, to examine the transcriptomic basis of the interaction between D. melanogaster and entomopathogenic nematodes. We have employed next-generation RNA sequencing (RNAseq) to investigate the transcriptomic profile of D. melanogaster larvae in response to infection by S. carpocapsae symbiotic (carrying ...


2d Nmr Structural Study Of A Dna Duplex Containing Two Unnatural Base Pairs, Weston Preising 2017 University of San Diego

2d Nmr Structural Study Of A Dna Duplex Containing Two Unnatural Base Pairs, Weston Preising

Undergraduate Honors Theses

DNA is the genetic blueprint responsible for the traits of living organisms. The "genetic alphabet" consists of four molecules called nucleobases, represented by the letters A, T, G, and C strung together in a "strand." A DNA duplex consists of two "strands" held together such that A is across from T and G across from C, referred to A-T and G-C "base pairs". Recently, the genetic alphabet or code has been expanded by synthetic biologists in an effort to unveil new insights to the machinery of DNA replication, and potentially develop new medicines to cure diseases like HIV. The new ...


Estimation Of The True Evolutionary Distance Under The Fragile Breakage Model., Nikita Alexeev, Max A Alekseyev 2017 George Washington University

Estimation Of The True Evolutionary Distance Under The Fragile Breakage Model., Nikita Alexeev, Max A Alekseyev

Computational Biology Institute

BACKGROUND: The ability to estimate the evolutionary distance between extant genomes plays a crucial role in many phylogenomic studies. Often such estimation is based on the parsimony assumption, implying that the distance between two genomes can be estimated as the rearrangement distance equal the minimal number of genome rearrangements required to transform one genome into the other. However, in reality the parsimony assumption may not always hold, emphasizing the need for estimation that does not rely on the rearrangement distance. The distance that accounts for the actual (rather than minimal) number of rearrangements between two genomes is often referred to ...


Understanding The Structure Of Amyloid Fibrils Using Atomic Force Microscopy (Afm) To Design New Therapeutic Strategies For Neurodegenerative Diseases, Sumeyra Gokalp, Michelle Foster 2017 University of Massachusetts Boston

Understanding The Structure Of Amyloid Fibrils Using Atomic Force Microscopy (Afm) To Design New Therapeutic Strategies For Neurodegenerative Diseases, Sumeyra Gokalp, Michelle Foster

UMass Center for Clinical and Translational Science Research Retreat

Amyloid fibrils are misfolded proteins that are irreversible once they are formed. In human beings, there are different kinds of proteins that form into amyloid fibrils and are associated with several degenerative diseases. For example, insulin, Huntington, Amyloid β-42 and α- synuclein proteins are linked with Type-2 Diabetes, Huntington’s, Alzheimer’s and Parkinson’s diseases, respectively. The mechanism for the misfolding and creation of the fibrils is thought to be the same for all of these proteins. Hen Egg White Lysozyme (HEWL) is a low-cost and widely recognized model protein to work with to help us understand the mechanisms ...


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