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Defined Structure (defined + structure)
Selected AbstractsIdentifying and reducing error in cluster-expansion approximations of protein energiesJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 16 2010Seungsoo Hahn Abstract Protein design involves searching a vast space for sequences that are compatible with a defined structure. This can pose significant computational challenges. Cluster expansion is a technique that can accelerate the evaluation of protein energies by generating a simple functional relationship between sequence and energy. The method consists of several steps. First, for a given protein structure, a training set of sequences with known energies is generated. Next, this training set is used to expand energy as a function of clusters consisting of single residues, residue pairs, and higher order terms, if required. The accuracy of the sequence-based expansion is monitored and improved using cross-validation testing and iterative inclusion of additional clusters. As a trade-off for evaluation speed, the cluster-expansion approximation causes prediction errors, which can be reduced by including more training sequences, including higher order terms in the expansion, and/or reducing the sequence space described by thecluster expansion. This article analyzes the sources of error and introduces a method whereby accuracy can be improved by judiciously reducing the described sequence space. The method is applied to describe the sequence,stability relationship for several protein structures: coiled-coil dimers and trimers, a PDZ domain, and T4 lysozyme as examples with computationally derived energies, and SH3 domains in amphiphysin-1 and endophilin-1 as examples where the expanded pseudo-energies are obtained from experiments. Our open-source software package Cluster Expansion Version 1.0 allows users to expand their own energy function of interest and thereby apply cluster expansion to custom problems in protein design. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] Amino terminal interaction in the prion protein identified using fusion to green fluorescent proteinJOURNAL OF NEUROCHEMISTRY, Issue 5 2003Yongxiu Yao Abstract In contrast to the well-characterized carboxyl domain, the amino terminal half of the mature cellular prion protein has no defined structure. Here, following fusion of mouse prion protein fragments to green fluorescence protein as a reporter of protein stability, we report extreme variability in fluorescence level that is dependent on the prion fragment expressed. In particular, exposure of the extreme amino terminus in the context of a truncated prion protein molecule led to rapid degradation, whereas the loss of only six amino terminal residues rescued high level fluorescence. Study of the precise endpoints and residue identity associated with high fluorescence suggested a domain within the amino terminal half of the molecule defined by a long-range intramolecular interaction between 23KKRPKP28 and 143DWED146 and dependent upon the anti-parallel ,-sheet ending at residue 169 and normally associated with the structurally defined carboxyl terminal domain. This previously unreported interaction may be significant for understanding prion bioactivity and for structural studies aimed at the complete prion structure. [source] H93G myoglobin cavity mutant as versatile template for modeling heme proteins: Magnetic circular dichroism studies of thiolate- and imidazole-ligated complexesBIOPOLYMERS, Issue 4-5 2002John H. Dawson Abstract Recent ligand binding and spectroscopic investigations of the myoglobin H93G cavity mutant are reviewed, revealing it to be a versatile template for the preparation of model heme complexes of defined structure. The H93G myoglobin cavity mutant is shown to be capable of forming mixed ligand adducts because of the difference in accessibility of the two sides of the ferric heme iron. With imidazole bound in the proximal cavity, H93G myoglobin also forms reasonably stable oxyferrous and oxoferryl derivatives, thereby providing a potential system to use for the study of such complexes with proximal ligands other than imidazole. In addition, thiolate-ligated ferric H93G derivatives are described that serve as spectroscopic models for the high-spin ferric state of cytochrome P450. All of the complexes described are characterized with magnetic circular dichroism spectroscopy, and they are compared to the appropriate derivatives of native myoglobin and P450. © 2002 Wiley Periodicals, Inc. Biopolymers (Biospectroscopy) 67: 200,206, 2002 [source] Cell Shape Normalization, Dendrite Orientation, and Melanin Production of Normal and Genetically Altered (Haploinsufficient NF1)-Melanocytes by Microstructured Substrate InteractionsCHEMPHYSCHEM, Issue 1 2004Simon Jungbauer Abstract Little is known about how functional regulation failure in genetically altered cells is influenced by topographical confinement of cells, a situation often present in tissues in vivo. We used cultured melanocytes derived from human skin samples as a model system for such investigations. Normal melanocytes have a very well defined shape consisting of a cell body and two dendrites arranged 180° relative to each other. In contrast, neurofibromin 1-melanocytes (NF1-melanocytes) have up to a 50,% reduction of neurofibromin 1, which results in an altered morphology that can be easily measured. NF1-melanocytes deviate from the defined structure of normal melanocytes by forming more than two dendrites per cell. We show that morphology consequences of genetically altered melanocytes can be canceled if cells interact with substrates microstructured by stripes that apply mechanophysical signals in the form of physical topography. The strength of the mechanophysical signal was varied systematically by increasing the height of the microstructures. Melanocytes respond to surface topographical features that are larger than 50 nm and have lateral confinements smaller 4 ,m. The response of normal and NF1-melanocytes to different topographies was analyzed quantitatively by determining density distributions for the number of dendrites per cell, the angles between dendrites, and the orientation imprinted in the substrate. The synthesis of melanin, a pigment produced by melanocytes, differs in the case of genetically altered NF1- and normal melanocytes. In both cases, the interaction with microstripes enhanced melanin production significantly. This enhanced melanin production is speculated to be caused by the mechanical stabilization of the dendrites by substrate guidance. [source] New strategies for polymer development in pharmaceutical science , a short reviewJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2001A. Godwin We are developing synthetic polymers for pharmaceutical and medical applications. These applications can be broadly grouped on how the polymer will be utilized e.g. material, excipient or molecule. Our focus is to develop polymers with more defined structures that are based on biological, physicochemical and/or materials criteria. Strategies are being developed to more efficiently optimize structure,property correlations during preclinical development. We describe two examples of our research on pharmaceutical polymer development: narrow molecular weight distribution (MWD) homopolymeric precursors which can be functionalized to give families of narrow MWD homo- and co-polymers, and hydrolytically degradable polymers. [source] | ||||||||||