48 research outputs found
Prediction of the permeability of neutral drugs inferred from their solvation properties
Determination of drug absorption is an important component of the drug discovery and development process in that it plays a key role in the decision to promote drug candidates to clinical trials. We have developed a method that, on the basis of an analysis of the dynamic distribution of water molecules around a compound obtained by molecular dynamics simulations, can compute a parameter-free value that correlates very well with the compound permeability measured using the human colon adenocarcinoma (Caco-2) cell line assay
Efficient and Accurate Modeling of Conformational Transitions in Proteins: The Case of c-Src Kinase
The theoretical computational modeling of large conformational transitions occurring in biomolecules still represents a challenge. Here, we present an accurate "in silico" description of the activation and deactivation mechanisms of human c-Src kinases, a fundamental process regulating several crucial cell functions. Our results clearly show that by applying an efficient and automated algorithm able to drive the molecular dynamics (MD) sampling along the pathway between the two c-Src conformational states - the active state and the inactive state - it is possible to accurately describe, at reduced computational costs, the molecular mechanism underlying these large conformational rearrangements. This procedure, combining the MD simulations with the sampling along the well-defined principal motions connecting the two conformational states, allows to provide a description well beyond the present computational limits, and it is easily applicable to different systems where the structures of both the initial and final states are known
High throughput interactome determination via sulfur anomalous scattering
We propose a novel approach to detect the binding between proteins making use
of the anomalous diffraction of natively present heavy elements inside the
molecule 3D structure. In particular, we suggest considering sulfur atoms
contained in protein structures at lower percentages than the other atomic
species. Here, we run an extensive preliminary investigation to probe both the
feasibility and the range of usage of the proposed protocol. In particular, we
(i) analytically and numerically show that the diffraction patterns produced by
the anomalous scattering of the sulfur atoms in a given direction depend
additively on the relative distances between all couples of sulfur atoms. Thus
the differences in the patterns produced by bound proteins with respect to
their non-bonded states can be exploited to rapidly assess protein complex
formation. Next, we (ii) carried out analyses on the abundances of sulfurs in
the different proteomes and molecular dynamics simulations on a representative
set of protein structures to probe the typical motion of sulfur atoms. Finally,
we (iii) suggest a possible experimental procedure to detect protein-protein
binding. Overall, the completely label-free and rapid method we propose may be
readily extended to probe interactions on a large scale even between other
biological molecules, thus paving the way to the development of a novel field
of research based on a synchrotron light source.Comment: 9 pages, 4 figure
Does blood type affect the COVID-19 infection pattern?
Among the many aspects that characterize the COVID-19 pandemic, two seem
particularly challenging to understand: (i) the great geographical differences
in the degree of virus contagiousness and lethality which were found in the
different phases of the epidemic progression, and (ii) the potential role of
the infected people's blood type in both the virus infectivity and the
progression of the disease. A recent hypothesis could shed some light on both
aspects. Specifically, it has been proposed that in the subject-to-subject
transfer SARS-CoV-2 conserves on its capsid the erythrocytes' antigens of the
source subject. Thus these conserved antigens can potentially cause an immune
reaction in a receiving subject that has previously acquired specific
antibodies for the source subject antigens. This hypothesis implies a blood
type-dependent infection rate. The strong geographical dependence of the blood
type distribution could be, therefore, one of the factors at the origin of the
observed heterogeneity in the epidemics spread. Here, we present an
epidemiological deterministic model where the infection rules based on blood
types are taken into account and compare our model outcomes with the exiting
worldwide infection progression data. We found an overall good agreement, which
strengthens the hypothesis that blood types do play a role in the COVID-19
infection.Comment: 6 figures, 4 table
Exploring the Association Between Sialic Acid and SARS-CoV-2 Spike Protein Through a Molecular Dynamics-Based Approach
Recent experimental evidence demonstrated the capability of SARS-CoV-2 Spike protein to bind sialic acid molecules, which was a trait not present in SARS-CoV and could shed light on the molecular mechanism used by the virus for the cell invasion. This peculiar feature has been successfully predicted by in-silico studies comparing the sequence and structural characteristics that SARS-CoV-2 shares with other sialic acid-binding viruses, like MERS-CoV. Even if the region of the binding has been identified in the N-terminal domain of Spike protein, so far no comprehensive analyses have been carried out on the spike-sialic acid conformations once in the complex. Here, we addressed this aspect performing an extensive molecular dynamics simulation of a system composed of the N-terminal domain of the spike protein and a sialic acid molecule. We observed several short-lived binding events, reconnecting to the avidic nature of the binding, interestingly occurring in the surface Spike region where several insertions are present with respect to the SARS-CoV sequence. Characterizing the bound configurations via a clustering analysis on the Principal Component of the motion, we identified different possible binding conformations and discussed their dynamic and structural properties. In particular, we analyze the correlated motion between the binding residues and the binding effect on the stability of atomic fluctuation, thus proposing regions with high binding propensity with sialic acid
Shape Complementarity Optimization of Antibody-Antigen Interfaces: the Application to SARS-CoV-2 Spike Protein
Many factors influence biomolecules binding, and its assessment constitutes
an elusive challenge in computational structural biology. In this respect, the
evaluation of shape complementarity at molecular interfaces is one of the main
factors to be considered. We focus on the particular case of antibody-antigen
complexes to quantify the complementarities occurring at molecular interfaces.
We relied on a method we recently developed, which employs the 2D Zernike
descriptors, to characterize investigated regions with an ordered set of
numbers summarizing the local shape properties. Collected a structural dataset
of antibody-antigen complexes, we applied this method and we statistically
distinguished, in terms of shape complementarity, pairs of interacting regions
from non-interacting ones. Thus, we set up a novel computational strategy based
on \textit{in-silico} mutagenesis of antibody binding site residues. We
developed a Monte Carlo procedure to increase the shape complementarity between
the antibody paratope and a given epitope on a target protein surface. We
applied our protocol against several molecular targets in SARS-CoV-2 spike
protein, known to be indispensable for viral cell invasion. We, therefore,
optimized the shape of template antibodies for the interaction with such
regions. As the last step of our procedure, we performed an independent
molecular docking validation of the results of our Monte Carlo simulations.Comment: 13 pages, 4 figure
A Shearless microfluidic device detects a role in mechanosensitivity for awcon neuron in Caenorhabditis elegans
AWC olfactory neurons are fundamental for chemotaxis toward volatile attractants in Caenorhabditis elegans. Here, it is shown that AWC(ON) responds not only to chemicals but also to mechanical stimuli caused by fluid flow changes in a microfluidic device. The dynamics of calcium events are correlated with the stimulus amplitude. It is further shown that the mechanosensitivity of AWC(ON) neurons has an intrinsic nature rather than a synaptic origin, and the calcium transient response is mediated by TAX-4 cGMP-gated cation channel, suggesting the involvement of one or more "odorant" receptors in AWC(ON) mechano-transduction. In many cases, the responses show plateau properties resembling bistable calcium dynamics where neurons can switch from one stable state to the other. To investigate the unprecedentedly observed mechanosensitivity of AWC(ON) neurons, a novel microfluidic device is designed to minimize the fluid shear flow in the arena hosting the nematodes. Animals in this device show reduced neuronal activation of AWC(ON) neurons. The results observed indicate that the tangential component of the mechanical stress is the main contributor to the mechanosensitivity of AWC(ON). Furthermore, the microfluidic platform, integrating shearless perfusion and calcium imaging, provides a novel and more controlled solution for in vivo analysis both in micro-organisms and cultured cells
Differences in the organization of interface residues tunes the stability of the SARS-CoV-2 spike-ACE2 complex
The continuous emergence of novel variants represents one of the major problems in dealing with the SARS-CoV-2 virus. Indeed, also due to its prolonged circulation, more than ten variants of concern emerged, each time rapidly overgrowing the current viral version due to improved spreading features. As, up to now, all variants carry at least one mutation on the spike Receptor Binding Domain, the stability of the binding between the SARS-CoV-2 spike protein and the human ACE2 receptor seems one of the molecular determinants behind the viral spreading potential. In this framework, a better understanding of the interplay between spike mutations and complex stability can help to assess the impact of novel variants. Here, we characterize the peculiarities of the most representative variants of concern in terms of the molecular interactions taking place between the residues of the spike RBD and those of the ACE2 receptor. To do so, we performed molecular dynamics simulations of the RBD-ACE2 complexes of the seven variants of concern in comparison with a large set of complexes with different single mutations taking place on the RBD solvent-exposed residues and for which the experimental binding affinity was available. Analyzing the strength and spatial organization of the intermolecular interactions of the binding region residues, we found that (i) mutations producing an increase of the complex stability mainly rely on instaurating more favorable van der Waals optimization at the cost of Coulombic ones. In particular, (ii) an anti-correlation is observed between the shape and electrostatic complementarities of the binding regions. Finally, (iii) we showed that combining a set of dynamical descriptors is possible to estimate the outcome of point mutations on the complex binding region with a performance of 0.7. Overall, our results introduce a set of dynamical observables that can be rapidly evaluated to probe the effects of novel isolated variants or different molecular systems