Protein dynamics

In this Masters thesis computational modelling techniques were employed to investigate iron-free apo-Lactoferrin (apo-Lf) structural conformation changes in the presence of variant temperature and pH. These conditions represent the environment most milk protein goes through in food processing and the production of food products.

162p runthenight04 02-02-2023 8 3   Download

The thesis is organised as follows: Chapter 1 comprises the literature review of protein structure, amyloid fibrils and of the effect of nanomaterials on protein aggregation. Chapter 2 reviews the computational methods used to perform simulations and analysis. Chapter 3 comprises my published article on benchmarking forcefields and sampling methods for disordered proteins using amylin as a case study. Chapter 4 comprises my published article on the effect of oxidation on the properties of graphene oxide flakes in solution.

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The thesis is structured as follows: In Chapter 1, the scientific literature is summarized within the scope of this study. Chapter 2 provides a comprehensive overview of the principles of the applied computational approaches in this study. Chapter 3 identifies the important residues of the LsIA/α7 nAChR complex that affect the interactions between the toxin and the membrane protein due to C-terminal carboxylation of LsIA. The effects of C-terminal modification of LsIA on interactions with α3β2 nAChR, involved in cardiovascular diseases, were also investigated in Chapter 4.

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Nicotinamide N-methyltransferase (NNMT), a key cytoplasmic protein in the human body, is accountable to catalyze the nicotinamide (NCA) N1 -methylation through S-adenosyl-L-methionine (SAM) as a methyl donor, which has been linked to many diseases. Although extensive studies have concerned about the biological aspect, the detailed mechanism study of the enzyme function, especially in the part of protein dynamics is lacking.

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Porcine heart cytoplasmic malate dehydrogenase (s-MDH) is a dimeric protein (2 · 35 kDa). We have studied equilibrium unfolding and refolding of s-MDH using activity assay, fluorescence, far-UV and near-UV circular dichroism (CD) spectroscopy, hydrophobic probe-1-anilino8-napthalene sulfonic acid binding, dynamic light scattering, and chromatographic (HPLC) techniques. The unfolding and refolding transitions are reversible and show the presence of two equilibrium intermediate states.

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Many biological C-H activation reactions exhibit nonclassical kinetic isotope effects (KIEs). These nonclassical KIEs are too large (kH/kD 7) and/or exhibit unusual temperature dependence such that the Arrhenius prefactor KIEs (AH/AD) fall outside of the semiclassical range near unity. The focus of this minireview is to discuss such KIEs within the context of the environmentally coupled hydrogen tunneling model.

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This review describes studies of particular enzymatically catalyzed reactions to investigate the possibility that catalysis is mediated by protein dynamics. That is, evolution has crafted the protein backbone of the enzyme to direct vibrations in such a fashion to speed reaction. The review presents the theoretical approach we have used to investigate this problem, but it is designed for the nonspecialist.

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Laboratory for Lipoprotein Chemistry and 4Flanders Interuniversity Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine, Department of Biochemistry, Ghent University, Belgium; 2Laboratory of Biomolecular Dynamics, Katholieke Universiteit Leuven, Belgium; 3Ecole Normale Supe´rieure, Paris, France Penetratin is a 16-amino-acid peptide, derived from the homeodomain of antennapedia, a Drosophila transcription factor, which can be used as a vector for the intracellular delivery of peptides or oligonucleotides....

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DNA transactions in eukaryotes require that proteins gain access to target sequences packaged in chromatin. Further, interactions between distinct nucleoprotein complexes are often required to generate higher-order structures. Here, we employed two prokaryotic site-specific recombination systems to investigate how chromatin packaging affects the assembly of nucleoprotein structures of different complexities at more than 30 genomic loci. The dynamic nature of chromatin permitted protein–DNA and DNA–DNA interactions for sites of at least 34 bp in length.

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Chromatin is a highly dynamic structure that plays an essential role in regulating all nuclear processes that utilize the DNA template including DNA repair, replication, transcription and recombination. Thus, the mechanisms by which chromatin structures are assembled and modified are questions of broad interest. This minireview will focus on two groups of proteins: (a) histone chaperones and (b) ATPdependent chromatin remodeling machines, that co-operate to assemble DNA and histone proteins into chromatin....

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Lipid rafts are liquid-ordered membrane microdomains with a unique protein and lipid composition found on the plasma membrane of most, if not all, mammalian cells. A large number of signalling molecules are concentrated within rafts, which have been proposed to function as signalling centres capable of facilitating efficient and specific signal transduction. This review summarizes current knowledge regarding the composition, structure, and dynamic nature of lipid rafts, as well as a number of different signalling path- ways that are compartmentalized within these microdomains....

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Flavoproteins are ubiquitous redox proteins that are involved in many biological processes.In the majority of flavoproteins, the flavin cofactor is tightlybut noncovalently bound.Reversible dissociation of flavoproteins into apo-proteinandflavinprostheticgroupyields valuable insights in flavoprotein folding, functionandmechanism.Replacement of the natural cofactorwithartificial flavins has proved tobe especially useful for the determination of the solvent acces-sibility, polarity, reaction stereochemistry and dynamic behaviour of flavoprotein active sites....

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cAMP receptor protein (CRP), allosterically activated by cAMP, regulates the expression of several genes inEscheri-chia coli. As binding of cAMP leads to undefined conform-ational changes in CRP, we performed a steady-state and time-resolved fluorescence study to showhow the binding of the ligand influences the structure and dynamics of the protein. We used CRP mutants containing a single trypto-phan residue at position 85 or 13, and fluorescently labeled with 1,5-I-AEDANS attached toCys178.

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Dynamic protein–protein interactions are involved in most physiological processes and, in particular, for the formation of multiprotein signaling complexes at transmembrane receptors, adapter proteins and effector mole-cules. Because the unregulated induction of signaling complexes has sub-stantial clinical relevance, the investigation of these complexes is an active area of research.

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Retinol-binding protein transports retinol, and circulates in the plasma as a macromolecular complex with the protein transthyretin. Under acidic con-ditions retinol-binding protein undergoes a transition to the molten globule state, and releases the bound retinol ligand. A biased molecular dynamics simulation method has been used to generate models for the ensemble of conformers populated within this molten globule state.

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Heteronuclear NMR relaxation measurements and hydro-gen exchange data have been used to characterize protein dynamics in the presence or absence of stabilizing solutes from hyperthermophiles. Rubredoxin from Desulfovibrio gigaswas selected as a model protein and the effect of diglycerol phosphate on its dynamic behaviour was studied. The presence of 100 mMdiglycerol phosphate induces a fourfold increase in the half-life for thermal denaturation ofD.

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One of the most drastic post-translational modification of proteins in eu-karyotic cells is poly(ADP-ribosyl)ation, catalysed by a family enzymes termed poly(ADP-ribose) polymerases (PARPs). In the human genome, 18 different genes have been identified that all encode PARP family members.

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Human cells contain two homologs of the yeast RAD23 protein, hHR23A and hHR23B, which participate in the DNA repair process. hHR23B hou-ses a domain (residues 277–332, called XPCB) that binds specifically and directly to the xeroderma pigmentosum group C protein (XPC) to initiate nucleotide excision repair (NER). This domain shares sequence homology with a heat shock chaperonin-binding motif that is also found in the stress-inducible yeast phosphoprotein STI1.

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The solution structure ofNereis diversicolorsarcoplasmic calcium-binding protein (NSCP) in the calcium-bound form was determined by NMR spec-troscopy, distance geometry and simulated annealing. Based on 1859 NOE restraints and 262 angular restraints, 17 structures were generated with a rmsd of 0.87 A ˚ from the mean structure. The solution structure, which is highly similar to the structure obtained by X-ray crystallography, includes two open EF-hand domains, which are in close contact through their hydrophobic surfaces....

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Post-translational modifications, such as phosphorylation and acetylation of the tumour suppressor protein p53, elicit important effects on the func-tion and the stability of the resultant protein. However, as phosphorylation and acetylation are dynamic events subject to complex controls, elucidating the relationships between phosphorylation and acetylation is difficult.

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