Informed classification of sweeteners/bitterants compounds via explainable machine learning

Perception of taste is an emergent phenomenon arising from complex molecular interactions between chemical compounds and specific taste receptors. Among all the taste perceptions, the dichotomy of sweet and bitter tastes has been the subject of several machine learning studies for classification purposes. While previous studies have provided accurate sweeteners/bitterants classifiers, there is ample scope to enhance these models by enriching the understanding of the molecular basis of bitter-sweet tastes. Towards these goals, our study focuses on the development and testing of several machine learning strategies coupled with the novel SHapley Additive exPlanations (SHAP) for a rational sweetness/bitterness classification. This allows the identification of the chemical descriptors of interest by allowing a more informed approach toward the rational design and screening of sweeteners/bitterants. To support future research in this field, we make all datasets and machine learning models publicly available and present an easy-to-use code for bitter-sweet taste prediction

Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamics

Abstract Background Molecular phenomena driving pathological aggregation in neurodegenerative diseases are not completely understood yet. Peculiar is the case of Spinocerebellar Ataxia 3 (SCA3) where the conformational properties of the AT-3 N-terminal region, also called Josephin Domain (JD), play a key role in the first step of aggregation, having the JD an amyloidogenic propensity itself. For this reason, unraveling the intimate relationship between JD structural features and aggregation tendency may lead to a step forward in understanding the pathology and rationally design a cure. In this connection, computational modeling has demonstrated to be helpful in exploring the protein molecular dynamics and mechanism of action. Results Conformational dynamics of the JD is here finely investigated by replica exchange molecular dynamics simulations able to sample the microsecond time scale and to provide both a thermodynamic and kinetic description of the protein conformational changes. Accessible structural conformations of the JD have been identified in: open, intermediate and closed like arrangement. Data indicated the closed JD arrangement as the most likely protein arrangement. The protein transition from closed toward intermediate/open states was characterized by a rate constant higher than 700\ua0ns. This result also explains the inability of classical molecular dynamics to explore transitions from closed to open JD configuration on a time scale of hundreds of nanoseconds. Conclusion This work provides the first kinetic estimation of the JD transition pathway from open-like to closed-like arrangement and vice-versa, indicating the closed-like arrangement as the most likely configuration for a JD in water environment. More widely, the importance of our results is also underscored considering that the ability to provide a kinetic description of the protein conformational changes is a scientific challenge for both experimental and theoretical approaches to date. Reviewers This article was reviewed by Oliviero Carugo, Bojan Zagrovic

Conformational dynamics and stability of u-shaped and s-shaped amyloid β assemblies

Alzheimer’s disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ1–40 and Aβ1–42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aβ1–40 peptides can only assume U-shaped conformations while Aβ1–42 can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped Aβ17–42 small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils

Cell Penetrating Peptide Adsorption on Magnetite and Silica Surfaces: A Computational Investigation

Magnetic nanoparticles (MNPs) represent one of the most promising materials as they can act as a versatile platform in the field of bionanotechnology for enhanced imaging, diagnosis, and treatment of various diseases. Silica is the most common compound for preparing coated iron oxide NPs since it improves colloidal stability and the binding affinity for various organic molecules. Biomolecules such as cell penetrating peptides (CPPs) might be employed to decorate MNPs, combining their promising physicochemical properties with a cell penetrating ability. In this work, a computational investigation on adsorption of Antennapedia homeodomain-derived penetrating peptide (pAntp) on silica and magnetite (MAG) surfaces is presented. By employing umbrella sampling molecular dynamics, we provided a quantitative estimation of the pAntp-surface adsorption free energy to highlight the influence of surface hydroxylation state on the adsorption mechanism. The interaction between peptide and surface has shown to be mainly driven by electrostatics. In case of MAG surface, also an important contribution of van der Waals (VdW) attraction was observed. Our data suggest that a competitive mechanism between MNPs and cell membrane might partially inhibit the CPP to carry out its membrane penetrating function

computational molecular modelling as a platform for a deeper understanding of protein dynamics and rational drug design

Elucidating structural features of protein aggregation at molecular level may provide novel opportunities for overarching therapeutic approaches such as blocking common aggregation-induced cellular toxicity pathways. In this context molecular modelling stimulates further research on amyloid aggregation modulators and modelling platforms can be used to test the efficiency of potential aggregation inhibitors aimed at destabilizing/reducing the stability of the amyloidogenic protein

Protein environment : A crucial triggering factor in josephin domain aggregation: The role of 2,2,2-trifluoroethanol

The protein ataxin-3 contains a polyglutamine stretch that triggers amyloid aggregation when it is expanded beyond a critical threshold. This results in the onset of the spinocerebellar ataxia type 3. The protein consists of the globular N-terminal Josephin domain and a disordered C-terminal tail where the polyglutamine stretch is located. Expanded ataxin-3 aggregates via a two-stage mechanism: first, Josephin domain self-association, then polyQ fibrillation. This highlights the intrinsic amyloidogenic potential of Josephin domain. Therefore, much effort has been put into investigating its aggregation mechanism(s). A key issue regards the conformational requirements for triggering amyloid aggregation, as it is believed that, generally, misfolding should precede aggregation. Here, we have assayed the effect of 2,2,2-trifluoroethanol, a co-solvent capable of stabilizing secondary structures, especially α-helices. By combining biophysical methods and molecular dynamics, we demonstrated that both secondary and tertiary JD structures are virtually unchanged in the presence of up to 5% 2,2,2-trifluoroethanol. Despite the preservation of JD structure, 1% of 2,2,2-trifluoroethanol suffices to exacerbate the intrinsic aggregation propensity of this domain, by slightly decreasing its conformational stability. These results indicate that in the case of JD, conformational fluctuations might suffice to promote a transition towards an aggregated state without the need for extensive unfolding, and highlights the important role played by the environment on the aggregation of this globular domain

The Role of Structural Polymorphism in Driving the Mechanical Performance of the Alzheimer's Beta Amyloid Fibrils

Alzheimer's Disease (AD) is related with the abnormal aggregation of amyloid β-peptides Aβ1−40 and Aβ1−42, the latter having a polymorphic character which gives rise to U- or S-shaped fibrils. Elucidating the role played by the nanoscale-material architecture on the amyloid fibril stability is a crucial breakthrough to better understand the pathological nature of amyloid structures and to support the rational design of bio-inspired materials. The computational study here presented highlights the superior mechanical behavior of the S-architecture, characterized by a Young's modulus markedly higher than the U-shaped architecture. The S-architecture showed a higher mechanical resistance to the enforced deformation along the fibril axis, consequence of a better interchain hydrogen bonds' distribution. In conclusion, this study, focusing the attention on the pivotal multiscale relationship between molecular phenomena and material properties, suggests the S-shaped Aβ1−42 species as a target of election in computational screen/design/optimization of effective aggregation modulators

T regulatory cells are markers of disease activity in multiple sclerosis patients

FoxP3+ Treg cells are believed to play a role in the occurrence of autoimmunity and in the determination of clinical recurrences. Contradictory reports are, however, available describing frequency and function of Treg cells during autoimmune diseases. We examined, by both polychromatic flow cytometry, and real-time RT-PCR, several Treg markers in peripheral blood mononuclear cells from patients with multiple sclerosis (MS), an autoimmune disease affecting the central nervous system. We found that Tregs, as defined by CD25, CD39, FoxP3, CTLA4, and GITR expression, were significantly decreased in stable MS patients as compared to healthy donors, but, surprisingly, restored to normal levels during an acute clinical attack. We conclude that Treg cells are not involved in causing clinical relapses, but rather react to inflammation in the attempt to restore homeostasis