Photoinduced inverse spin Hall effect in Pt/Ge(001) at room temperature

We performed photoinduced inverse spin Hall effect (ISHE) measurements on a Pt/Ge(001) junction at room temperature. The spin-oriented electrons, photogenerated at the direct gap of Ge using circularly polarized light, provide a net spin current which yields an electromotive field E_ISHE in the Pt layer. Such a signal is clearly detected at room temperature despite the strong {\Gamma} to L scattering which electrons undergo in the Ge conduction band. The ISHE signal dependence on the exciting photon energy is in good agreement with the electron spin polarization expected for optical orientation at the direct gap of Ge

Increased throughput in methods for simulating protein ligand binding and unbinding

By incorporating full flexibility and enabling the quantification of crucial parameters such as binding free energies and residence times, methods for investigating protein-ligand binding and unbinding via molecular dynamics provide details on the involved mechanisms at the molecular level. While these advancements hold promise for impacting drug discovery, a notable drawback persists: their relatively time-consuming nature limits throughput. Herein, we survey recent implementations which, employing a blend of enhanced sampling techniques, a clever choice of collective variables, and often machine learning, strive to enhance the efficiency of new and previously reported methods without compromising accuracy. Particularly noteworthy is the validation of these methods that was often performed on systems mirroring real-world drug discovery scenarios

Systematic Exploitation of Multiple Receptor Conformations for Virtual Ligand Screening

The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and to prioritize for experimental testing a comparatively small and diverse set of compounds with expected activity against a target. Several studies have pointed out that the performance of virtual ligand screening can be improved by taking into account receptor flexibility. Here, we systematically assess how multiple crystallographic receptor conformations, a powerful way of discretely representing protein plasticity, can be exploited in screening protocols to separate binders from non-binders. Our analyses encompass 36 targets of pharmaceutical relevance and are based on actual molecules with reported activity against those targets. The results suggest that an ensemble receptor-based protocol displays a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart. Moreover, such a protocol can be engineered not only to enrich a higher number of active compounds, but also to enhance their chemical diversity. Finally, some clear indications can be gathered on how to select a subset of receptor conformations that is most likely to provide the best performance in a real life scenario

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

Patient symptom relief is often heavily influenced by the residence time of the inhibitor–target complex. For the human muscarinic receptor 3 (hMR3), tiotropium is a long-acting bronchodilator used in conditions such as asthma or chronic obstructive pulmonary disease (COPD). The mechanistic insights into this inhibitor remain unclear; specifically, the elucidation of the main factors determining the unbinding rates could help develop the next generation of antimuscarinic agents. Using our novel unbinding algorithm, we were able to investigate ligand dissociation from hMR3. The unbinding paths of tiotropium and two of its analogues, N-methylscopolamin and homatropine methylbromide, show a consistent qualitative mechanism and allow us to identify the structural bottleneck of the process. Furthermore, our machine learning-based analysis identified key roles of the ECL2/TM5 junction involved in the transition state. Additionally, our results point to relevant changes at the intracellular end of the TM6 helix leading to the ICL3 kinase domain, highlighting the closest residue L482. This residue is located right between two main protein binding sites involved in signal transduction for hMR3′s activation and regulation. We also highlight key pharmacophores of tiotropium that play determining roles in the unbinding kinetics and could aid toward drug design and lead optimization

Pure spin currents in Ge probed by inverse spin-Hall effect

We perform photoinduced inverse spin-Hall effect (ISHE) measurements on a Pt/Ge(001) junction at room temperature. The spin-oriented electrons are photogenerated at the Γ point of the Ge Brillouin zone using circularly-polarized light. After the ultrafast Γ−L scattering in the Ge conduction band, which partially preserves the spin polarization, electrons diffuse into the Pt layer where spin-dependent scattering with Pt nuclei yields a transverse electromotive field EISHE. The ISHE signal dependence as a function of the incident photon energy is investigated and interpreted in the frame of a one-dimensional spin drift-diffusion model. This allows estimating the electron spin lifetime at the L-valleys to be τs=1 ns

Paramagnon-Enhanced Spin Currents in a Lattice near the Curie Point

Spin transport phenomena have been shown to be highly enhanced when the temperature approaches the Curie point of the material sustaining a spin flow. Here we propose a simple - yet unifying - explanation for such enhancements, based on a random-phase model accounting for the spin fluctuations within a ferromagnetic material in the paramagnetic phase. We show that pure spin currents carried by conduction electrons injected into a paramagnetic lattice of mutually interacting localized magnetic moments can be enhanced close to the Curie temperature by the exchange interaction between the lattice sites and the non vanishing spin density associated with the spin current. The latter partially aligns the magnetic moments of the lattice, generating a flow of paramagnons that contribute to the total spin current, resulting in an enhancement that can be as large as tenfold

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

Patient symptom relief is often heavily influenced by the residence time of the inhibitor-target complex. For the human muscarinic receptor 3 (hMR3), tiotropium is a long-acting bronchodilator used in conditions such as asthma or chronic obstructive pulmonary disease (COPD). The mechanistic insights into this inhibitor remain unclear; specifically, the elucidation of the main factors determining the unbinding rates could help develop the next generation of antimuscarinic agents. Using our novel unbinding algorithm, we were able to investigate ligand dissociation from hMR3. The unbinding paths of tiotropium and two of its analogues, N-methylscopolamin and homatropine methylbromide, show a consistent qualitative mechanism and allow us to identify the structural bottleneck of the process. Furthermore, our machine learning-based analysis identified key roles of the ECL2/TM5 junction involved in the transition state. Additionally, our results point to relevant changes at the intracellular end of the TM6 helix leading to the ICL3 kinase domain, highlighting the closest residue L482. This residue is located right between two main protein binding sites involved in signal transduction for hMR3's activation and regulation. We also highlight key pharmacophores of tiotropium that play determining roles in the unbinding kinetics and could aid toward drug design and lead optimization

Optical generation of pure spin currents at the indirect gap of bulk Si

We report on the optical generation of a pure spin current at the indirect gap of bulk Si at room temperature in the photon energy range comprised between 1.2 and 1.8 eV. Spin-polarized electrons are promoted to the Δ-valleys of the Si Brillouin zone by circularly polarized light. The photo-generated spin current is then detected by exploiting a Schottky Pt/Si(001) junction: spin-polarized electrons diffuse toward the Pt/Si interface and enter the Pt layer where the spin current is converted into a transverse electromotive field through the inverse spin-Hall effect (ISHE). The photon energy dependence of the ISHE signal is interpreted in the frame of a one-dimensional spin drift-diffusion model, which allows estimating the electron spin lifetime to be τs=15±5 ns

Multitarget drug design strategy in Alzheimer’s disease: focus on cholinergic transmission and amyloid-β aggregation

Background: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network. Results: By exploiting the multitarget approach, the present study provides new molecules able to target the cholinergic pathway, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit Aβ aggregation. Conclusions: These new compounds emerged as a suitable starting point for a further optimization process