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Molecular Dynamic Simulations (molecular + dynamic_simulation)
Selected AbstractsDesign of (Gd-DO3A)n -polydiamidopropanoyl-peptide nucleic acid- D(Cys-Ser-Lys-Cys) magnetic resonance contrast agentsBIOPOLYMERS, Issue 12 2008Nariman V. Amirkhanov Abstract We hypothesized that chelating Gd(III) to 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetylamide (DO3A) on peptide nucleic acid (PNA) hybridization probes would provide a magnetic resonance genetic imaging agent capable of hybridization to a specific mRNA. Because of the low sensitivity of Gd(III) as an magnetic resonance imaging (MRI) contrast agent, a single Gd-DO3A complex per PNA hybridization agent could not provide enough contrast for detection of cancer gene mRNAs, even at thousands of mRNA copies per cell. To increase the Gd(III) shift intensity of MRI genetic imaging agents, we extended a novel DO3An -polydiamidopropanoyl (PDAPm) dendrimer, up to n = 16, from the N-terminus of KRAS PNA hybridization agents by solid phase synthesis. A C-terminal D(Cys-Ser-Lys-Cys) cyclized peptide analog of insulin-like growth factor 1 (IGF1) was included to enable receptor-mediated cellular uptake. Molecular dynamic simulation of the (Gd-DO3A-AEEA)16 -PDAP4 -AEEA2 - KRAS PNA-AEEA- D(Cys-Ser-Lys-Cys) genetic imaging nanoparticles in explicit water yielded a pair correlation function similar to that of PAMAM dendrimers, and a predicted structure in which the PDAP dendron did not sequester the PNA. Thermal melting measurements indicated that the size of the PDAP dendron included in the (DO3A-AEEA)n -PDAPm -AEEA2 - KRAS PNA-AEEA- D(Cys-Ser-Lys-Cys) probes (up to 16 Gd(III) cations per PNA) did not depress the melting temperatures (Tm) of the complementary PNA/RNA hybrid duplexes. The Gd(III) dendrimer PNA genetic imaging agents in phantom solutions displayed significantly greater T1 relaxivity per probe (r1 = 30.64 ± 2.68 mM,1 s,1 for n = 2, r1 = 153.84 ± 11.28 mM,1 s,1 for n = 8) than Gd-DTPA (r1 = 10.35 ± 0.37 mM,1 s,1), but less than that of (Gd-DO3A)32 -PAMAM dendrimer (r1 = 771.84 ± 20.48 mM,1 s,1) (P < 0.05). Higher generations of PDAP dendrimers with 32 or more Gd-DO3A residues attached to PNA- D(Cys-Ser-Lys-Cys) genetic imaging agents might provide greater contrast for more sensitive detection. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 1061,1076, 2008. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] Molecular dynamic simulations of nanomechanic chaperone peptide and effects of in silico His mutations on nanostructured functionJOURNAL OF PEPTIDE SCIENCE, Issue 11 2008Abolfazl Barzegar Abstract The nanoscale peptide YSGVCHTDLHAWHGDWPLPVK exhibits molecular chaperone activity and prevents protein aggregation under chemical and/or thermal stress. Here, His mutations of this peptide and their impact on chaperone activity were evaluated using theoretical techniques. Molecular dynamic (MD) simulations with simulated annealing (SA) of different mutant nanopeptides were employed to determine the contribution of the scaffolding His residues (H45, H49, H52), when mutated to Pro, on chaperone action in vitro. The in silico mutations of His residues to Pro (H45P, H49P, H52P) revealed loss of secondary ordered strand structure. However, a small part of the strand conformation was formed in the middle region of the native chaperone peptide. The His-to-Pro mutations resulted in decreased gyration radius (Rg) values and surface accessibility of the mutant peptides under the simulation times. The invariant dihedral angle (,) values and the disrupting effects of the Pro residues indicated the coil conformation of mutant peptides. The failure of the chaperone-like action in the Pro mutant peptides was consistent with their decreased effective accessible surfaces. The high variation of , value for His residues in native chaperone peptide leads to high flexibility, such as a minichaperone acting as a nanomachine at the molecular level. Our findings demonstrate that the peptide strand conformation motif with high flexibility at nanoscale is critical for chaperone activity. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd. [source] NMR-derived model of interconverting conformations of an ICAM-1 inhibitory cyclic nonapeptideCHEMICAL BIOLOGY & DRUG DESIGN, Issue 3 2003L.O. Sillerud Abstract:, We have produced by phage-display a disulfide-linked cyclic nonapeptide (inhibitory peptide-01, IP01), CLLRMRSIC, that binds to intracellular adhesion molecule-1 (ICAM-1) and blocks binding to its counter-structure, leukocyte functional antigen-1 (LFA-1). As a first step towards improving its pharmacologic properties, we have performed a structural and functional analysis of this peptide inhibitor to determine the features relevant to ICAM-1 binding. We report here the solution model of our initial product, IP01, as derived from two-dimensional nuclear magnetic resonance (NMR) restraints and molecular modeling. Distance and dihedral angle restraints, generated from nuclear Overhauser effect spectroscopy (NOESY) and one-dimensional-NMR experiments respectively, were used to generate an ensemble of structures using distance geometry and simulated annealing. Molecular dynamic simulations produced three interconverting conformational families consistent with the NMR-derived constraints. We describe these conformations and their mechanism of interconversion. Furthermore, we have measured the IC50 s of a series of inhibitors generated from IP01 through alanine substitution of each residue. These results show that the L2-L3-R4-M5-R6 segment is functionally active, conformationally flexible, and contains a ,-turn involving residues R4-S7, while the C1-C9-I8-S7 segment is less functionally-active but adopts a more defined solution conformation, consistent with a scaffolding function. This model will be useful for designing nonpeptide-based organic inhibitors with improved pharmacologic properties. [source] A study on thermal conductivity of a quasi-ordered liquid layer on a solid substrateHEAT TRANSFER - ASIAN RESEARCH (FORMERLY HEAT TRANSFER-JAPANESE RESEARCH), Issue 7 2007Xiao-Yan Shi Abstract In the present paper, a study on thermal conductivity of a quasi-ordered liquid layer on a solid surface was performed by molecular dynamic simulation. Results showed that the motion of the molecules and their radial distribution function in the quasi-ordered liquid layer were similar to those of solid molecules. By using the Green,Kubo formula, the thermal conductivity of the layer was calculated. It was found that it increased with the increase of the parameters of ordering. The size effect and the influence of the boundary condition were also discussed. © 2007 Wiley Periodicals, Inc. Heat Trans Asian Res, 36(7): 429,434, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/htj.20171 [source] Bacillus subtilis Esterase (BS2) and its Double Mutant Have Different Selectivity in the Removal of Carboxyl Protecting GroupsADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 14-15 2009Efrosini Barbayianni Abstract An esterase from Bacillus subtilis (BS2) and its double mutant E188W/M193C quickly hydrolyze n -butyl, n -propyl, methoxyethyl and allyl esters. The wild-type BS2 preferentially removes such esters from the ,-position of glutamate diesters, while the engineered enzyme has a reversed selectivity removing esters from the ,-position of glutamate diesters. Automated docking and molecular dynamic simulations were performed to understand the molecular reason for the different regioselectivity. [source] Ramachandran-type plots for glycosidic linkages: Examples from molecular dynamic simulations using the Glycam06 force fieldJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 6 2009Amanda M. Salisburg Abstract The goals of this article are to (1) provide further validation of the Glycam06 force field, specifically for its use in implicit solvent molecular dynamic (MD) simulations, and (2) to present the extension of G.N. Ramachandran's idea of plotting amino acid phi and psi angles to the glycosidic phi, psi, and omega angles formed between carbohydrates. As in traditional Ramachandran plots, these carbohydrate Ramachandran-type (carb-Rama) plots reveal the coupling between the glycosidic angles by displaying the allowed and disallowed conformational space. Considering two-bond glycosidic linkages, there are 18 possible conformational regions that can be defined by (,, ,, ,) and (,, ,, ,), whereas for three-bond linkages, there are 54 possible regions that can be defined by (,, ,, ,, ,) and (,, ,, ,, ,). Illustrating these ideas are molecular dynamic simulations on an implicitly hydrated oligosaccharide (700 ns) and its eight constituent disaccharides (50 ns/disaccharide). For each linkage, we compare and contrast the oligosaccharide and respective disaccharide carb-Rama plots, validate the simulations and the Glycam06 force field through comparison to experimental data, and discuss the general trends observed in the plots. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009 [source] Complexation of aminoglutethimide with native and modified cyclodextrinsJOURNAL OF PHYSICAL ORGANIC CHEMISTRY, Issue 10 2009Michal Nowakowski Abstract Complexations of R(+) and RS(+/,)aminoglutethimide (AGT), the drug used in a treatment of breast and prostate cancer with native and modified cyclodextrins (, -CD, , -CD, , -CD, 2,6-di- O -methyl- , -CD (DM- , -CD), 2,3,6-tri- O -methyl- , -CD (TM- , -CD) and carboxymethyl- , -CD (CM- , -CD)) were studied. The stability constants were determined with UV,Vis spectrophotometric method at pH 9.0. The NMR data obtained for TM- , -CD suggest that the complexation of AGT is possible from both sides of CD molecule. This was confirmed by molecular dynamic simulations. Copyright © 2009 John Wiley & Sons, Ltd. [source] Spinodal Decomposition in Ternary Systems with Significantly Different Component DiffusivitiesMACROMOLECULAR THEORY AND SIMULATIONS, Issue 6 2007Abdulrahman A. Alfarraj Abstract A numerical method for simulating spinodal decomposition in ternary systems with order-of-magnitude differences in diffusion coefficients is presented. The method has been partially verified by molecular dynamic simulations and gives results equivalent to the standard technique when the diffusivities are equal. A two-dimensional simulation of an asymmetric polymer/polymer/polymer system reproduces an experimentally observed bimodal distribution of dispersed-phase particle sizes. The ripening exponent for the larger particles is near the expected value of 0.33, but that for the smaller particles is only about 0.1. The method was also used for a polymer/polymer/solvent system. [source] Interpreting Experimental Data by Using Molecular Simulation Instead of Model BuildingCHEMISTRY - A EUROPEAN JOURNAL, Issue 26 2009Zrinka Gattin Abstract A proper description of the conformational equilibrium of polypeptides or proteins is essential for a correct description of their function. The conformational ensembles from 16 molecular dynamic simulations of two ,- heptapeptides were used to interpret the primary NMR data, which were also compared to a set of NMR model structures (see graphic). One of the most used spectroscopic techniques for resolving the structure of a biomolecule, such as a protein or peptide, is NMR spectroscopy. Because only NMR signal intensities and frequencies are measured in the experiment, a conformational interpretation of the primary data, that is, measured data, is not straightforward, especially for flexible molecules. It is hampered by the occurrence of conformational and/or time-averaging, by insufficient number of experimental data and by insufficient accuracy of experimental data. All three problematic aspects of structure refinement based on NMR nuclear Overhauser effect (NOE) intensities and 3J coupling data are illustrated by using two ,-heptapeptides in methanol as an example. We have performed 16 molecular dynamics (MD) simulations between 20 to 100,ns in length of unrestrained and NOE distance-restrained cases (instantaneous and time-averaged) of two ,-heptapeptides with a central ,-HAla(,-OH) amino acid in methanol at two different temperatures using two different GROMOS force-field parameter sets, 45,A3 and 53,A6. The created conformational ensembles were used to interpret the primary NMR data on these molecules. They also were compared to a set of NMR model structures derived by single-structure refinement in vacuo by using standard techniques. It is shown that the conformational interpretation of measured experimental data can be significantly improved by using unrestrained, instantaneous and time-averaged restrained MD simulations of the peptides by using a thermodynamically calibrated force field and by explicitly including solvent degrees of freedom. [source] | ||||||||||