1,721,226 research outputs found
Molecular dynamics using p-threads
No full textIn this paper we report our work on a SM-MIMD architecture clustered as four SMP machines of the MPI version of the GROMACS V1.5.1. We used a cluster of Digital AS4100 interconnected with Memory Channel and Digital MPI V1.4 as hardware testbed. We developed a new threaded version of MPI GROMACS and it permitted us to measure perfomance and scalability of the new code in real MD simulation runs. The new code open a way to further improve the MD simulations to date giving a way to estimate its scalability on M-SMP clustered machine and similar parallel architectures
X-ray absorption study of the solvation structure of Cu 2+ in methanol and dimethyl sulfoxide
No full textThe solvation structure of Cu2+ in methanol (MeOH) and dimethyl sulfoxide (DMSO) has been determined by studying both the extended X-ray absorption fine structure (EXAFS) and the X-ray absorption near-edge structure (XANES) regions of the K-edge absorption spectra. The EXAFS technique has been found to provide a very accurate determination of the next-neighbor coordination distances, but it is inconclusive in the determination of the coordination numbers and polyhedral environment. Conversely, quantitative analysis of the XANES spectra unambiguously shows the presence of an average 5-fold coordination in both the MeOH and DMSO solution, ruling out the usually proposed octahedral Jahn–Teller distorted geometry. The EXAFS and XANES techniques provide coherent values of the Cu–O first-shell distances that are coincident in the two solvents. This investigation shows that the combined analysis of the EXAFS and XANES data allows a reliable determination of the structural properties of electrolyte solutions, which is very difficult to achieve with other experimental techniques
HECT-Type E3 Ubiquitin Ligases in Cancer
No full textUbiquitination, a post-translational modification that involves a covalent attachment of ubiquitin to a protein substrate, is essential for cellular homeostatic maintenance. At the end of a three-enzyme cascade, E3 ubiquitin ligases (E3s) recruit substrates and promote or directly catalyze ubiquitin transfer to targets. These enzymes largely determine the specificity of the ubiquitination reaction. Genetic alteration, abnormal expression, or dysfunction of E3s account for the occurrence and progression of human cancers. Indeed, excessive degradation of relevant tumor-suppressor molecules and impaired disposal of oncogenic proteins have been linked to tumorigenesis. This review focuses on the emerging roles of HECT-type E3s in tumorigenesis, and emphasizes how perturbations of these enzymes contribute to cancer pathogenesis
Structure and hydration of BamHI DNA recognition site: a molecular dynamics investigation
No full textThe results of a 3-ns molecular dynamics simulation of the dodecamer duplex d(TATGGATCCATA)2 recognized by the BamHI endonuclease are presented here. The DNA has been simulated as a flexible molecule using an AMBER force field and the Ewald summation method, which eliminates the undesired effects of truncation and permits evaluation of the full effects of electrostatic forces. The starting B conformation evolves toward a configuration quite close to that observed through x-ray diffraction in its complex with BamHI. This configuration is fairly stable and the Watson-Crick hydrogen bonds are well maintained over the simulation trajectory. Hydration analysis indicates a preferential hydration for the phosphate rather than for the ester oxygens. Hydration shells in both the major and minor groove were observed. In both grooves the C-G pairs were found to be more hydrated than A-T pairs. The “spine of hydration” in the minor groove was clear. Water residence times are longer in the minor groove than in the major groove, although relatively short in both cases. No special long values are observed for sites where water molecules were observed by x-ray diffraction, indicating that water molecules having a high probability of being located in a specific site are also fast-exchanging
Conformational Dynamics of Lysine Methyltransferase Smyd2. Insights into the Different Substrate Crevice Characteristics of Smyd2 and Smyd3
No full textAbstract: Smyd2, the SET and MYND domain containing proteinlysine methyltransferase, targets histone and nonhistone substrates.Methylation of nonhistone substrates has direct implications in cancerdevelopment and progression. Dynamic regulation of Smyd2 activityand the structural basis of broad substrate specificity still remain elusive.Herein, we report on extensive molecular dynamics simulations on a fulllength Smyd2 in the presence and absence of AdoMet cofactor(covering together 1.3 μs of sampling), and the accompanyingconformational transitions. Additionally, dynamics of the C-terminaldomain (CTD) and structural features of substrate crevices of Smyd2 and Smyd3 are compared. The CTD of Smyd2 exhibitsconformational flexibility in both states. In the holo form, however, it undergoes larger hinge motions resulting in more openedconfigurations than the apo form, which is confined around the partially open starting X-ray configuration. AdoMet bindingtriggers increased elasticity of the CTD leading Smyd2 to adopt fully opened configurations, which completely exposes thesubstrate binding crevice. These long-range concerted motions highlight Smyd2’s ability to target substrates of varying sizes.Substrate crevices of Smyd2 and Smyd3 show distinct features in terms of spatial, hydration, and electrostatic properties thatemphasize their characteristic modes of substrates interaction and entry pathways for inhibitor binding. On the whole, our studyshows how the elasticity and hinge motion of the CTD regulate its functional role and underpin the basis of broad substratespecificity of Smyd2. We also highlight the specific structural principles that guide substrate and inhibitor binding to Smyd2 andSmyd
DEVELOPMENT AND VALIDATION OF AN INTEGRATED COMPUTATIONAL APPROACH FOR THE STUDY OF IONIC SPECIES IN SOLUTION BY MEANS OF EFFECTIVE TWO-BODY POTENTIALS. THE CASE OF ZN2+, NI2+, AND CO2+ IN ....
No full textStructural Investigation of Lanthanoid Coordination: a Combined XANES and Molecular Dynamics Study
No full textThis is the first systematic study exploring the potentiality of the X-ray absorption near edge structure (XANES) technique as a structural tool for systems containing lanthanoid(III) ions. A quantitative analysis of the XANES spectra at the K- and L3-edges has been carried out for three hydrated lanthanoid(III) ions, namely, Yb, Nd, and Gd, in aqueous solution and in the isostructural trifluoromethanesulfonate salts. The structural and dynamic properties of the hydrated lanthanoid(III) ions in aqueous solution have been investigated by a combined experimental-theoretical approach employing X-ray absorption spectroscopy and molecular dynamics (MD) simulations. This method allows one to perform a quantitative analysis of the XANES spectra of ionic solutions using a proper description of the thermal and structural fluctuations. XANES spectra have been computed starting from the MD trajectory, without carrying out any minimization in the structural parameter space. A comparative K- and L3-edge XANES data analysis is presented, demonstrating the clear advantages of the L3-edge XANES analysis over the K-edge studies for structural investigations of lanthanoid compounds. The second hydration shells provide a detectable contribution to the L3-edge spectra while the K-edge data are insensitive to the more distant coordination spheres because of the strong damping and broadening of the signal caused by the extremely large core hole widths. The XANES technique has been found to be a new valuable tool for the structural characterization of metal complexes both in the solid and in the liquid state, especially in the presence of low symmetry
Structural dynamics of V3 loop in a trimeric ambiance, a molecular dynamics study on gp120-CD4 trimeric mimic.
No full textEntry of HIV virus into the host cell is initiated by the interaction of its surface exposed gp120 protein with the cell surface CD4 receptor and a co-receptor that can be either CCR5 or CXCR4. The third variable region (V3 loop) of gp120 has an important role in co-receptor selection by gp120 and forms an epitope for neutralizing antibodies. In this work the dynamical behavior of the V3 loop in a trimeric environment has been investigated by generating an atomistic trimer model of gp120–CD4 complex and has been compared with the result of a monomeric gp120–CD4 complex. The main results coming from this work are that the three V3 loops belonging to the three subunits of the trimer display a different dynamical behavior in terms of its flexibility, spatial orientation, motion along the principal modes, conformations, solvent exposure and electrostatic potential distribution. We propose that the ability of the V3 loop to present, in the trimeric environment, simultaneous multiple alternative conformations that increase its capability of co-receptor recognition, is at least in part due to the effect of electrostatic potential generated by two subunits over the third one
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