A Functional Interaction Between Y674-R685 Region of the SARS-CoV-2 Spike Protein and the Human α7 Nicotinic Receptor (preprint)

The α7 nicotinic acetylcholine receptor (nAChR) is present in neuronal and non-neuronal cells and has anti-inflammatory actions. Molecular dynamics simulations suggested that α7 nAChR interacts with a region of the SARS-CoV-2 spike protein (S), and a potential contribution of nAChRs to COVID-19 pathophysiology has been proposed. We applied whole-cell and single-channel recordings to determine whether the Y674-R685 region of the S protein can directly affect α7 nAChR function. The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive inhibitor. It activates α7 nAChRs, in line with our previous molecular dynamics simulations showing favorable binding of this accessible region of the S protein to the nAChR agonist binding site. However, activation requires the presence of positive allosteric modulators that enhance open probability, indicating very low efficacy. The main effect of the S fragment on α7 nAChR is a negative modulation, which is evidenced by a profound decrease in the durations of channel openings and activation episodes and in the amplitude of macroscopic responses elicited by ACh. Our study identifies a novel functional interaction between α7 nAChR and a region of the S protein, thus providing molecular foundations for exploring the involvement of nAChRs in COVID-19 pathophysiology.

A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human α7 Nicotinic Receptor (preprint)

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection relies on the binding of the viral spike protein (S) to angiotensin-converting enzyme 2 in host cells. Regions of the S protein have been suggested to interact with nicotinic acetylcholine receptors (nAChRs), and a potential contribution of nAChRs to COVID-19 pathophysiology has been proposed. α7 nAChR is an interesting candidate target since it is present in neuronal and non-neuronal cells, including immune cells, and has anti-inflammatory actions. We here identified a novel direct functional interaction between the α7 nAChR and a region of the S protein (Y674-R685). The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive inhibitor. It activates the α7 nAChR, in line with our previous molecular dynamics simulations showing favorable binding of this accessible region of the S protein to the nAChR agonist binding pocket. However, activation requires the presence of positive allosteric modulators that enhance channel opening probability, indicating very low activation efficacy. The S fragment exerts an additional inhibition, which may be the predominant effect on α7 responses. This study reveals a functional interaction between α7 and the Y674-R685 fragment of the S protein, which opens doors for exploring the involvement of nAChRs in COVID-19 pathophysiology.

"How Come You Don't Call Me?" Smartphone Communication App Usage as an Indicator of Loneliness and Social Well-Being across the Adult Lifespan during the COVID-19 Pandemic.

Loneliness and lack of social well-being are associated with adverse health outcomes and have increased during the COVID-19 pandemic. Smartphone communication data have been suggested to help monitor loneliness, but this requires further evidence. We investigated the informative value of smartphone communication app data for predicting subjective loneliness and social well-being in a sample of 364 participants ranging from 18 to 78 years of age (52.2% female; mean age = 42.54, SD = 13.22) derived from the CORONA HEALTH APP study from July to December 2020 in Germany. The participants experienced relatively high levels of loneliness and low social well-being during the time period characterized by the COVID-19 pandemic. Apart from positive associations with phone call use times, smartphone communication app use was associated with social well-being and loneliness only when considering the age of participants. Younger participants with higher use times tended to report less social well-being and higher loneliness, while the opposite association was found for older adults. Thus, the informative value of smartphone communication use time was rather small and became evident only in consideration of age. The results highlight the need for further investigations and the need to address several limitations in order to draw conclusions at the population level.

The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour (preprint)

The SARS-CoV-2 spike protein is the first contact point between the SARS-CoV-2 virus and host cells and mediates membrane fusion. Recently, a fatty acid binding site was identified in the spike (Toelzer et al. Science 2020). The presence of linoleic acid at this site modulates binding of the spike to the human ACE2 receptor, stabilizing a locked conformation of the protein. Here, dynamical-nonequilibrium molecular dynamics simulations reveal that this fatty acid site is coupled to functionally relevant regions of the spike, some of them far from the fatty acid binding pocket. Removal of a ligand from the fatty acid binding site significantly affects the dynamics of distant, functionally important regions of the spike, including the receptor-binding motif, furin cleavage site and fusion-peptide-adjacent regions. The results also show significant differences in behaviour between clinical variants of the spike: e.g. the D614G mutation shows a significantly different conformational response for some structural motifs relevant for binding and fusion. The simulations identify structural networks through which changes at the fatty acid binding site are transmitted within the protein. These communication networks significantly involve positions that are prone to mutation, indicating that observed genetic variation in the spike may alter its response to linoleate binding and associated allosteric communication.

Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors and suggest subtype specificity (preprint)

Changeux et al. recently suggested that the SARS-CoV-2 spike (S) protein may interact with nicotinic acetylcholine receptors (nAChRs). Such interactions may be involved in pathology and infectivity. Here, we use molecular simulations of validated atomically detailed structures of nAChRs, and of the S protein, to investigate this nicotinic hypothesis. We examine the binding of the Y674-R685 loop of the S protein to three nAChRs, namely the human 4{beta}2 and 7 subtypes and the muscle-like {beta}{gamma}d receptor from Tetronarce californica. Our results indicate that Y674-R685 has affinity for nAChRs and the region responsible for binding contains the PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses. In particular, R682 has a key role in the stabilisation of the complexes as it forms interactions with loops A, B and C in the receptors binding pocket. The conformational behaviour of the bound Y674-R685 region is highly dependent on the receptor subtype, adopting extended conformations in the 4{beta}2 and 7 complexes and more compact ones when bound to the muscle-like receptor. In the 4{beta}2 and {beta}{gamma}d complexes, the interaction of Y674-R685 with the receptors forces the loop C region to adopt an open conformation similar to other known nAChR antagonists. In contrast, in the 7 complex, Y674-R685 penetrates deeply into the binding pocket where it forms interactions with the residues lining the aromatic box, namely with TrpB, TyrC1 and TyrC2. Estimates of binding energy suggest that Y674-R685 forms stable complexes with all three nAChR subtypes. Analyses of the simulations of the full-length S protein show that the Y674-R685 region is accessible for binding, and suggest a potential binding orientation of the S protein with nAChRs.