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

Influenza Vaccination in Patients with Rheumatoid Arthritis under treatment with TNFα Blockers or co-stimulus Inhibitor

Influenza vaccination in patients with rheumatoid arthritis under treatment with TNFα blockers or co-stimulus inhibitors Objective To evaluate the safety and the immunogenicity of the trivalent seasonal non-adjuvanted anti-influenza vaccine in rheumatoid arthritis RA patients receiving distinct classes of anti tumor necrosis factor -TNF agents or inhibitors of co-stimulus compared with patients with RA or SLE receiving DMARDs and healthy controls and the effect of a simultaneous 23valent anti-pneumococcal or pandemic monovalent MF59-H1N1adjuvanted vaccine. Methods 85 patients with RA, under treatment with TNFα blockers or inhibitors of co-stimulus, all with stable disease (under the same treatment during the last six months), were immunized at least once with nonadjuvanted trivalent influenza vaccine during three consecutive influenza seasons and compared with 42 HC. In the second season 30 RA patients (13 HC) received simultaneously also adjuvanted pandemic H1N1 vaccination. In the first and third season, instead, respectively 19 and 15 RA (10 and 6 HC) patients received simultaneously also polysaccaride pneumococcal vaccination. In the last season 9 RA and 16 SLE under treatment with DMARDS were also enrolled. Sera were analyzed by hemagglutination-inhibition (HAI) test, according to standard procedures, and vaccine immunogenicity was evaluated according to the Committee for Human Medicinal Products (CHMP) guidelines. Seroprotection, seroconversion (SC), geometric mean titre (GMT), GMT increase, T-reg cells, anti-nuclear antibodies (ANA), adverse events and disease acrivity (according to clinimetric indices) were evaluated at baseline and at 30 and 180 days after vaccination/s. In the second season a study on T cell memory subset modification and aspecific cellular immune response was performed in a patient soubgroup. Moreover the effect of the polisaccaride vaccine on cellular immune response has been analyzed on stimulated PBMC in vitro through cytofluorimetry and ELISA. Results Safety No severe adverse events, ANA appearance/increase or disease reactivation were observed during the 3 influenza seasons. Antibodies 2008/2009: RA patients did not fulfill any immunogenity criteria for A/Brisbane/59/07 (H1), 1 for B/Florida/4/06 , and 3 for A/Brisbane/10/07 (H3). HC, instead, met all the 3 criteria for A/Brisbane/59/07 (H1) and A/Brisbane/10/07 (H3) and only one for B/Florida/4/06. However, the mean increase in geometric mean titer was not statistically different between RA and HC for any antigen. 2009/2010: Both HC and RA patients fulfilled all the 3 immunogenity criteria for the seasonal (A/Brisbane/59/07 (H1) A/Brisbane/10/07 (H3) B/Brisbane/60/08) and the pandemic (A/California/7/2009 (H1)) antigens with no statistical difference between groups. 2010/2011: RA and SLE patients under treatment with DMARDS and HC fullfilled all the 3 immunogenity criteria, while RA under treatment with biological agents only 1 for A/Perth/16/09 (H3) and 2 for A/California/7/2009 (H1) and B/Brisbane/60/08. Increase in GMT versus H1(p 0.008) and H3 (p 0.046) was statistically different between RA on biological and HC and versus H1 (p 0.034) and B (p 0.003) between RA on biological and RA on DMARDS in subjects immunized only with influenza. Among HC and RA patients under treatment with DMARDS immunized also with pneumococcal vaccine no response was observed vs H3 compared to the complete response in subjects immunized with only influenza (HC p 0.034) No significant difference in vaccine response has been observed among the different groups of biological agents (Etanercept, Infliximab, adalimumab, abatacept) The cohort follow-up revealed increase in GMT and seroprotection rate for A but not for B antigens. Cell-mediated immunity An increase in Tregs, activated cytokine-producing cells, T naïve and CM subsets and a decrease in T EM and TD lymphocytes, 30 days after vaccination, was observed both in patients and controls. In vitro studies showed that the presence of the polysaccharide vaccine inhibits specific and aspecific cellular immune response in a dose-dependent manner. Conclusion Response to seasonal influenza vaccination in RA and SLE patients under treatment with DMARDS is comparable to HC. The suboptimal response in the first and third seasons both in RA patients under treatment with biological agents and HC could be partially due to the simultaneous pneumococcal vaccination. Adjuvanted influenza vaccine looks to be safe and able to achieve strong immunogenicity, comparable to HC, even in this group of patients. The increase at T1 in activated T cells reflects the predominant implication of Th1 response to vaccination

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

Network dilution and asymmetry in an efficient brain

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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

Molecular dynamics simulations reveal canonical conformations in different pMHC/TCR interactions

The major defense system against microbial pathogens in vertebrates is the adaptive immune response and represents an effective mechanism in cancer surveillance. T cells represent an essential component of this complex system. They can recognize myriads of antigens as short peptides (p) originated from the intracellular degradation of foreign proteins presented by major histocompatibility complex (MHC) proteins. The clonotypic T-cell antigen receptor (TCR) is specialized in recognizing pMHC and triggering T cells immune response. It is still unclear how TCR engagement to pMHC is translated into the intracellular signal that initiates T-cell immune response. Some work has suggested the possibility that pMHC binding induces in the TCR conformational changes transmitted to its companion CD3 subunits that govern signaling. The conformational changes would promote phosphorylation of the CD3 complex ζ chain that initiates signal propagation intracellularly. Here, we used all-atom molecular dynamics simulations (MDs) of 500 ns to analyze the conformational behavior of three TCRs (1G4, ILA1 and ILA1α1β1) interacting with the same MHC class I (HLA-A*02:01) bound to different peptides, and modelled in the presence of a lipid bilayer. Our data suggest a correlation between the conformations explored by the β-chain constant regions and the T-cell response experimentally determined. In particular, independently by the TCR type involved in the interaction, the TCR activation seems to be linked to a specific zone of the conformational space explored by the β-chain constant region. Moreover, TCR ligation restricts the conformational space the MHC class I groove

Investigating the side-chain structural organization behind the stability of protein folding and binding

What are the molecular mechanisms that dictate protein-protein binding stability and whether those are related to the ones behind protein fold stability are still largely open questions. Indeed, despite many past efforts, we still lack definitive models to account for experimental quantities like protein melting temperature or complex binding affinity. Here, we investigate and compare chemical and physical features on a dataset of protein with known melting temperature as well as a large dataset of protein-protein complexes with reliable experimental binding affinity. In particular, we probed the aminoacid composition and the organization of the network of intramolecular and intermolecular interaction energies among residues. We found that hydrophobic residues present on the protein surfaces are preferentially located in the binding regions, while charged residues behave oppositely. In addition, the abundance of polar amino acid like Serine and Proline correlates with the binding affinity of the complexes. Analysing the interaction energies we found that distant Coulombic interactions are responsible for thermal stability while the total inter-molecular van der Waals energy correlates with protein-protein binding affinity.Comment: 8 pages, 3 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