25 research outputs found
Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: conformational analysis and binding mode of multisite inhibitors
The critical role of BACE-1 in the formation of neurotoxic Ă-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimerâs disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challeng- ing. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragmentsâhuprine and rheinâ that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8â14, 154â169 and 307â318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable âfloppyâ pocket would enable the bind- ing of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligo- methylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications intro- duced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors
Can environment or allergy explain international variation in prevalence of wheeze in childhood?
Asthma prevalence in children varies substantially around the world, but the contribution of known risk factors to this international variation is uncertain. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two studied 8â12 year old children in 30 centres worldwide with parent-completed symptom and risk factor questionnaires and aeroallergen skin prick testing. We used multilevel logistic regression modelling to investigate the effect of adjustment for individual and ecological risk factors on the between-centre variation in prevalence of recent wheeze. Adjustment for single individual-level risk factors changed the centre-level variation from a reduction of up to 8.4% (and 8.5% for atopy) to an increase of up to 6.8%. Modelling the 11 most influential environmental factors among all children simultaneously, the centre-level variation changed little overall (2.4% increase). Modelling only factors that decreased the variance, the 6 most influential factors (synthetic and feather quilt, motherâs smoking, heating stoves, dampness and foam pillows) in combination resulted in a 21% reduction in variance. Ecological (centre-level) risk factors generally explained higher proportions of the variation than did individual risk factors. Single environmental factors and aeroallergen sensitisation measured at the individual (child) level did not explain much of the between-centre variation in wheeze prevalence
Anthropogenic Sources and their Environmental Impact to Surface Waters
Abstract Influence of the human beings to the nature initially was inexistent, but it increased continuously until the industri
Utilizing Machine Learning for Efficient Parameterization of Coarse Grained Molecular Force Fields
This work demonstrates the use of open literature data to force field paramterization via a novel approach applying Bayesian optimization. We have selected Dissipative Particle Dynamics (DPD) as the simulation method in this proof-of-concept work
Towards Low Cost Virtual Biological Laboratories: Molecular Modelling Simulation on Commodity Hardware.
Many essential cell processes, such as the conformation of embedded proteins, membrane permeability, interaction with drugs and signalling, are directly connected to the
molecular dynamics of cell membranes. The importance of this biology has led to an intensifying demand for hardware and software optimized models and tools, implemented
on commodity high performance low-cost hardware, in order to provide the scientific community with virtual low cost laboratories. In the light of these considerations, we implemented an accelerated version of a molecular dynamics coarse-grain lipid bilayers simulator on commodity Graphic Processing Units (GPU) architectures. The characteristics of this molecular dynamics model, such as new force fields for pair potentials that include an unconventional representation for water and charges, were particularly challenging. We introduced new algorithms and data structures required by coarse-grain models compared to atomistic ones, for the modelling of the integration timestep, neighbour list generation, and nonbonded
force interactions. We characterized the impact on performance of biological systems of differing complexity in terms of size, particle type and timestep. We also compared the simulations of many particle-type systems against single particle-type systems, to evaluate the overhead of additional structures needed to model more complex molecules. Moreover, we performed a detailed analysis on the profiling of the simulation code and its execution flows due to the computation of the non-bonded forces. Finally, we characterized the acceleration and accuracy of the simulations on three GPUs having
different computation capabilities and parallelism, achieving one order of magnitude faster simulation execution times
En-Bloc Excision of a Giant Chondrosarcoma of the Anterior Chest Wall Followed by Plastic Reconstruction of the Defect
CoCo-MD: A Simple and Effective Method for the Enhanced Sampling of Conformational Space
CoCo
(âcomplementary coordinatesâ) is a method for
ensemble enrichment based on principal component analysis (PCA) that
was developed originally for the investigation of NMR data. Here we
investigate the potential of the CoCo method, in combination with
molecular dynamics simulations (CoCo-MD), to be used more generally
for the enhanced sampling of conformational space. Using the alanine
penta-peptide as a model system, we find that an iterative workflow,
interleaving short multiple-walker MD simulations with long-range
jumps through conformational space informed by CoCo analysis, can
increase the rate of sampling of conformational space up to 10 times
for the same computational effort (total number of MD timesteps).
Combined with the reservoir-REMD method, free energies can be readily
calculated. An alternative, approximate but fast and practically useful,
alternative approach to unbiasing CoCo-MD generated data is also described.
Applied to cyclosporine A, we can achieve far greater conformational
sampling than has been reported previously, using a fraction of the
computational resource. Simulations of the maltose binding protein,
begun from the âopenâ state, effectively sample the
âclosedâ conformation associated with ligand binding.
The PCA-based approach means that optimal collective variables to
enhance sampling need not be defined in advance by the user but are
identified automatically and are adaptive, responding to the characteristics
of the developing ensemble. In addition, the approach does not require
any adaptations to the associated MD code and is compatible with any
conventional MD package