SARS-CoV-2 Spike Affinity and Dynamics Exclude the Strict Requirement of an Intermediate Host

SARS-CoV-2 proximal origin is still unclear, limiting the possibility of foreseeing other spillover events with pandemic potential. Here we propose an evolutionary model based on the thorough dissection of SARS-CoV-2 and RaTG13 - the closest bat ancestor - spike dynamics, kinetics and binding to ACE2. Our results indicate that both spikes share nearly identical, high affinities for Rhinolophus affinis bat and human ACE2, pointing out to negligible species barriers directly related to receptor binding. Also, SARS-CoV-2 spike shows a higher degree of dynamics and kinetics optimization that favors ACE2 engagement. Therefore, we devise an affinity-independent evolutionary process that likely took place in R. affinis bats and limits the eventual involvement of other animal species in initiating the pandemic to the role of vector.

Prenatal alcohol exposure disrupts hippocampal sharp‐wave ripple‐associated spike dynamics

Prenatal alcohol exposure (PAE) is among the most common developmental insults to the nervous system and is characterized by memory disruption. There is a pressing need to identify physiological alterations that help explain this memory impairment. Hippocampal sharp-wave ripples (SPW-Rs) are a compelling candidate for this purpose as they are the electrophysiological signatures of memory consolidation. We report that rats exposed to moderate prenatal alcohol display abnormalities restricted to SPW-R episodes that manifest as decreased recruitment of CA1 pyramidal cells and interneurons to SPW-R events, altered excitation during SPW-Rs, and decreased cell assembly activation rate. These differences observed at the single neuron and the population level may limit the ability of memory trace reactivation during SPW-Rs through the disruption of the intrinsic structure of cell sequences. Together, our results suggest that alterations in hippocampal SPW-R spike dynamics may underlie alcohol exposure-related memory deficits.

AI-driven multiscale simulations illuminate mechanisms of SARS-CoV-2 spike dynamics

We develop a generalizable AI-driven workflow that leverages heterogeneous HPC resources to explore the time-dependent dynamics of molecular systems. We use this workflow to investigate the mechanisms of infectivity of the SARS-CoV-2 spike protein, the main viral infection machinery. Our workflow enables more efficient investigation of spike dynamics in a variety of complex environments, including within a complete SARS-CoV-2 viral envelope simulation, which contains 305 million atoms and shows strong scaling on ORNL Summit using NAMD. We present several novel scientific discoveries, including the elucidation of the spike’s full glycan shield, the role of spike glycans in modulating the infectivity of the virus, and the characterization of the flexible interactions between the spike and the human ACE2 receptor. We also demonstrate how AI can accelerate conformational sampling across different systems and pave the way for the future application of such methods to additional studies in SARS-CoV-2 and other molecular systems.

Structures and function of locked conformations of SARS-CoV-2 spike

The spike protein (S) of SARS-CoV-2 has been observed in three distinct pre-fusion conformations: locked, closed and open. Of these, the locked conformation was not previously observed for SARS-CoV-1 S and its function remains poorly understood. Here we engineered a SARS-CoV-2 S protein construct “S-R/x3” to arrest SARS-CoV-2 spikes in the locked conformation by a disulfide bond. Using this construct we determined high-resolution structures revealing two distinct locked states, with or without the D614G substitution that has become fixed in the globally circulating SARS-CoV-2 strains. The D614G mutation induces a structural change in domain D from locked-1 to locked-2 conformation to alter spike dynamics, promoting transition into the closed conformation from which opening of the receptor binding domain is permitted. The transition from locked to closed conformations is additionally promoted by a change from low to neutral pH. We propose that the locked conformations of S are present in the acidic cellular compartments where virus is assembled and egresses. In this model, release of the virion into the neutral pH extracellular space would favour transition to the closed form which itself can stochastically transition into the open form. The S-R/x3 construct provides a tool for the further structural and functional characterization of the locked conformations of S, as well as how sequence changes might alter S assembly and regulation of receptor binding domain dynamics.

Linear Response of General Observables in Spiking Neuronal Network Models

We establish a general linear response relation for spiking neuronal networks, based on chains with unbounded memory. This relation allow us to predict the influence of a weak amplitude time dependent external stimuli on spatio-temporal spike correlations, from the spontaneous statistics (without stimulus) in a general context where the memory in spike dynamics can extend arbitrarily far in the past. Using this approach, we show how the linear response is explicitly related to the collective effect of the stimuli, intrinsic neuronal dynamics, and network connectivity on spike train statistics. We illustrate our results with numerical simulations performed over a discrete time integrate and fire model.

Управляемая нейроморфная динамика систем фазовой синхронизации

We consider the neuromorphic dynamics of a filter-free phase locked loop with a phase modulation of a reference oscillator. The transition from pulsed single-spike dynamics to the bursting dynamics can be easily controlled by changing the depth and frequency of phase modulation, as well as the gain factor along the ring of the phase locked loop. The possibility of implementing neuromorphic calculations of the "OR" type in the scheme of three phase locked loops mutually coupled through a common control circuit is shown. The presented results can be used in the design of hardware-implemented neuromorphic networks with increased frequency stability, resistant to noise influences.

Grid cell firing fields in a volumetric space

We investigated how entorhinal grid cells represent volumetric (three-dimensional) space. On a flat surface, grid cell firing fields are circular and arranged in a close-packed hexagonal array. In three dimensions, theoretical and computational work suggests that the most efficient configuration would be a regular close packing of spherical fields. We report that in rats exploring a cubic lattice, grid cells were spatially stable and maintained normal directional modulation, theta modulation and spike dynamics. However, while the majority of grid fields were spherical, they were irregularly arranged, even when only fields abutting the lower surface (equivalent to the floor) were considered. Thus, grid organization is shaped by the environment’s movement affordances, and may not need to be regular to support spatial computations.One Sentence SummaryIn rats exploring a volumetric space, grid cells are spatially modulated but their firing fields are irregularly arranged.