Water structure changes in oxime-mediated reactivation process of phosphorylated human acetylcholinesterase

c 2018 The Author(s). The role of water in oxime-mediated reactivation of phosphylated cholinesterases (ChEs) has been asked with recurrence. To investigate oximate water structure changes in this reaction, reactivation of paraoxon-inhibited human acetylcholinesterase (AChE) was performed by the oxime asoxime (HI-6) at different pH in the presence and absence of lyotropic salts: a neutral salt (NaCl), a strong chaotropic salt (LiSCN) and strong kosmotropic salts (ammonium sulphate and phosphate HPO42−). At the same time, molecular dynamic (MD) simulations of enzyme reactivation under the same conditions were performed over 100 ns. Reactivation kinetics showed that the low concentration of chaotropic salt up to 75 mM increased the percentage of reactivation of diethylphosphorylated AChE whereas kosmotropic salts lead only to a small decrease in reactivation. This indicates that water-breaker salt induces de-structuration of water molecules that are electrostricted around oximate ions. Desolvation of oximate favors nucleophilic attack on the phosphorus atom. Effects observed at high salt concentrations (>100 mM) result either from salting-out of the enzyme by kosmotropic salts (phosphate and ammonium sulphate) or denaturing action of chaotropic LiSCN. MDs simulations of diethylphosphorylated hAChE complex with HI-6 over 100 ns were performed in the presence of 100 mM (NH4)2SO4 and 50 mM LiSCN. In the presence of LiSCN, it was found that protein and water have a higher mobility, i.e. water is less organized, compared with the ammonium sulphate system. LiSCN favors protein solvation (hydrophobic hydration) and breakage of elelectrostricted water molecules around of oximate ion. As a result, more free water molecules participated to reaction steps accompanying oxime-mediated dephosphorylation

CADISHI: Fast parallel calculation of particle-pair distance histograms on CPUs and GPUs

We report on the design, implementation, optimization, and performance of the CADISHI software package, which calculates histograms of pair-distances of ensembles of particles on CPUs and GPUs. These histograms represent 2-point spatial correlation functions and are routinely calculated from simulations of soft and condensed matter, where they are referred to as radial distribution functions, and in the analysis of the spatial distributions of galaxies and galaxy clusters. Although conceptually simple, the calculation of radial distribution functions via distance binning requires the evaluation of $\mathcal{O}(N^2)$ particle-pair distances where $N$ is the number of particles under consideration. CADISHI provides fast parallel implementations of the distance histogram algorithm for the CPU and the GPU, written in templated C++ and CUDA. Orthorhombic and general triclinic periodic boxes are supported, in addition to the non-periodic case. The CPU kernels feature cache-blocking, vectorization and thread-parallelization to obtain high performance. The GPU kernels are tuned to exploit the memory and processor features of current GPUs, demonstrating histogramming rates of up to a factor 40 higher than on a high-end multi-core CPU. To enable high-throughput analyses of molecular dynamics trajectories, the compute kernels are driven by the Python-based CADISHI engine. It implements a producer-consumer data processing pattern and thereby enables the complete utilization of all the CPU and GPU resources available on a specific computer, independent of special libraries such as MPI, covering commodity systems up to high-end HPC nodes. Data input and output are performed efficiently via HDF5. (...) The CADISHI software is freely available under the MIT license.Comment: 19 page

Concentration Dependent Ion Selectivity in VDAC: A Molecular Dynamics Simulation Study

The voltage-dependent anion channel (VDAC) forms the major pore in the outer mitochondrial membrane. Its high conducting open state features a moderate anion selectivity. There is some evidence indicating that the electrophysiological properties of VDAC vary with the salt concentration. Using a theoretical approach the molecular basis for this concentration dependence was investigated. Molecular dynamics simulations and continuum electrostatic calculations performed on the mouse VDAC1 isoform clearly demonstrate that the distribution of fixed charges in the channel creates an electric field, which determines the anion preference of VDAC at low salt concentration. Increasing the salt concentration in the bulk results in a higher concentration of ions in the VDAC wide pore. This event induces a large electrostatic screening of the charged residues promoting a less anion selective channel. Residues that are responsible for the electrostatic pattern of the channel were identified using the molecular dynamics trajectories. Some of these residues are found to be conserved suggesting that ion permeation between different VDAC species occurs through a common mechanism. This inference is buttressed by electrophysiological experiments performed on bean VDAC32 protein akin to mouse VDAC

Structural insights into positive and negative allosteric regulation of a G protein-coupled receptor through protein-lipid interactions

Lipids are becoming known as essential allosteric modulators of G protein-coupled receptor (GPCRs). However, how they exert their efects on GPCR conformation at the atomic level is still unclear. In light of recent experimental data, we have performed several long-timescale molecular dynamics (MD) simulations, totalling 24 μs, to rigorously map allosteric modulation and conformational changes in the β2 adrenergic receptor (β2AR) that occur as a result of interactions with three diferent phospholipids. In particular, we identify diferent sequential mechanisms behind receptor activation and deactivation, respectively, mediated by specifc lipid interactions with key receptor regions. We show that net negatively charged lipids stabilize an active-like state of β2AR that is able to dock Gsα protein. Clustering of anionic lipids around the receptor with local distortion of membrane thickness is also apparent. On the other hand, net-neutral zwitterionic lipids inactivate the receptor, generating either fully inactive or intermediate states, with kinetics depending on lipid headgroup charge distribution and hydrophobicity. These chemical diferences alter membrane thickness and density, which diferentially destabilize the β2AR active state through lateral compression efects

Parallel Computation of Nonrigid Image Registration

Automatic intensity-based nonrigid image registration brings significant impact in medical applications such as multimodality fusion of images, serial comparison for monitoring disease progression or regression, and minimally invasive image-guided interventions. However, due to memory and compute intensive nature of the operations, intensity-based image registration has remained too slow to be practical for clinical adoption, with its use limited primarily to as a pre-operative too. Efficient registration methods can lead to new possibilities for development of improved and interactive intraoperative tools and capabilities. In this thesis, we propose an efficient parallel implementation for intensity-based three-dimensional nonrigid image registration on a commodity graphics processing unit. Optimization techniques are developed to accelerate the compute-intensive mutual information computation. The study is performed on the hierarchical volume subdivision-based algorithm, which is inherently faster than other nonrigid registration algorithms and structurally well-suited for data-parallel computation platforms. The proposed implementation achieves more than 50-fold runtime improvement over a standard implementation on a CPU. The execution time of nonrigid image registration is reduced from hours to minutes while retaining the same level of registration accuracy

Molecular dynamics simulation of guest diffusional and conformational behaviour of hexadecane-1,16-diol and hexadecane in urea inclusion compound models

Urea inclusion compounds are organic crystalline complexes that are potential candidates for molecular separator of long chain alkanes. A well-defined structure of the crystalline tunnel systems constructed from hydrogen bonding arrangement of urea molecules can be used to comprehend the fundamental aspects of processes involving ions or molecules transportation which play an important role in many physical, chemical and biological process taking place in a wide range of materials. This work endeavours to explore the diffusional behaviour of hexadecane-1,16-diol and hexadecane enclathration in urea tunnel architecture. The correlation of the diffusion mechanism with the guest’s structural and conformational properties was obtained using molecular dynamics simulation approach. Three-stage of model systems have been developed in this work. In the first phase, a single urea tunnel with inclusion of only one guest molecule was constructed. In the second phase, eleven guest molecules were included inside a single tunnel of rigid and nonrigid urea host molecules to observe the influence of the existence neighbours, i.e. the guest-guest intratunnel molecular interaction. In the third phase, four urea tunnels were constructed to take into account the effect of intertunnel interaction on the guests’ behavioural properties. It was found that hexadecane along the urea tunnel diffuse more rapidly than hexadecane-1,16-diol. The diffusion coefficients of hexadecane-1,16-diol in phase I, phase II of rigid and nonrigid and phase III model systems were 2.69 × 10-9 m2s-1, 1.83 × 10-10 m2s-1, 8.9 × 10-11 m2s-1, and 3.2 × 10-11 m2s-1, respectively, whilst those for hexadecane 1.96 × 10-8 m2s-1, 2.58 × 10-9 m2s-1, 7.15 × 10-10 m2s-1, and 5.36 × 10-10 m2s-1, respectively. The guests’ along urea tunnel exhibited slower diffusion with the value correlated well with experimental findings, as the size of the model systems tended to mimic the real system. Elucidation on the guest rotational pattern as the molecule translated within the confinement of urea tunnel found that the guest preferred to follow the right-handed spirals of the chiral urea hydrogen-bonded structure. Besides, the translational and rotational properties of the guests are much more pronounced in the nonrigid urea systems. It was suggested that restriction imposed on the rigid urea systems constrained the molecules from being in their best conformation, thus contributed to the overall observation on the guest structural and conformational behaviour. The asymmetrical G- and G+ distortion along the guest’s conformational energy which demonstrated the influence of urea chirality on the guest was notable on hexadecane-1,16-diol as compared to hexadecane. The variation in the diffusional and conformational properties evaluated in phase I, II and phase III model systems has highlighted the significant role of the guests’ functional groups, which in turn are associated to guest-guest intratunnel and intertunnel molecular interactions as well as the host-guest interaction. Molecular dynamics method offered significant fundamental knowledge associated with the structures and dynamics of the guest molecules in a well-defined urea nanoporous model systems that have important application in molecular separation and enantiomeric discrimination area