The animal reservoir of SARS-CoV-2 is unknown despite reports of SARS-CoV-2-related viruses in Asian Rhinolophus bats1–4, including the closest virus from R. affinis, RaTG13 (refs. 5,6), and pangolins7–9. SARS-CoV-2 has a mosaic genome, to which different progenitors contribute. The spike sequence determines the binding affinity and accessibility of its receptor-binding domain to the cellular angiotensin-converting enzyme 2 (ACE2) receptor and is responsible for host range10–12. SARS-CoV-2 progenitor bat viruses genetically close to SARS-CoV-2 and able to enter human cells through a human ACE2 (hACE2) pathway have not yet been identified, although they would be key in understanding the origin of the epidemic. Here we show that such viruses circulate in cave bats living in the limestone karstic terrain in northern Laos, in the Indochinese peninsula. We found that the receptor-binding domains of these viruses differ from that of SARS-CoV-2 by only one or two residues at the interface with ACE2, bind more efficiently to the hACE2 protein than that of the SARS-CoV-2 strain isolated in Wuhan from early human cases, and mediate hACE2-dependent entry and replication in human cells, which is inhibited by antibodies that neutralize SARS-CoV-2. None of these bat viruses contains a furin cleavage site in the spike protein. Our findings therefore indicate that bat-borne SARS-CoV-2-like viruses that are potentially infectious for humans circulate in Rhinolophus spp. in the Indochinese peninsula. A study reports the detection and characterization of SARS-CoV-2-like viruses in Laotian cave-dwelling bats that are also demonstrated to infect human cells through the ACE2 pathway. 

/pdf/bat-coronaviruses-related-to-sars-cov-2-and-infectious-for-2jxx1vkb.pdf

Bat coronaviruses related to SARS-CoV-2 and infectious for human cells

https://www.cell.com/biophysj/pdf/S0006-3495(12)00050-1.pdf

Depth of α-Synuclein in a Bilayer Determined by Fluorescence, Neutron Reflectometry, and Computation

Transmembrane (TM) proteins are major drug targets, but their structure determination, a prerequisite for rational drug design, remains challenging. Recently, the DeepMind's AlphaFold2 machine learning method greatly expanded the structural coverage of sequences with high accuracy. Since the employed algorithm did not take specific properties of TM proteins into account, the reliability of the generated TM structures should be assessed. Therefore, we quantitatively investigated the quality of structures at genome scales, at the level of ABC protein superfamily folds and for specific membrane proteins (e.g. dimer modeling and stability in molecular dynamics simulations). We tested template-free structure prediction with a challenging TM CASP14 target and several TM protein structures published after AlphaFold2 training. Our results suggest that AlphaFold2 performs well in the case of TM proteins and its neural network is not overfitted. We conclude that cautious applications of AlphaFold2 structural models will advance TM protein-associated studies at an unexpected level. 

/pdf/ins-and-outs-of-alphafold2-transmembrane-protein-structure-2q9tpvo8.pdf

Ins and outs of AlphaFold2 transmembrane protein structure predictions

The human ether-a-go-go related gene 1 (hERG1) K ion channel is a key element for the rapid component of the delayed rectified potassium current in cardiac myocytes. Since there are no crystal structures for hERG channels, creation and validation of its reliable atomistic models have been key targets in molecular cardiology for the past decade. In this study, we developed and vigorously validated models for open, closed, and open-inactivated states of hERG1 using a multistep protocol. The conserved elements were derived using multiple-template homology modeling utilizing available structures for Kv1.2, Kv1.2/2.1 chimera, and KcsA channels. Then missing elements were modeled with the ROSETTA De Novo protein-designing suite and further refined with all-atom molecular dynamics simulations. The final ensemble of models was evaluated for consistency to the reported experimental data from biochemical, biophysical, and electrophysiological studies. The closed state models were cross-validated against available e...

Modeling of open, closed, and open-inactivated states of the hERG1 channel: structural mechanisms of the state-dependent drug binding.

Photosynthetic antenna proteins can be thought of as “programmed solvents”, which bind pigments at specific mutual orientations, thus tuning the overall energetic landscape and ensuring highly efficient light-harvesting. While positioning of chlorophyll cofactors is well understood and rationalized by the principle of an “energy funnel”, the carotenoids still pose many open questions. Particularly, their short excited state lifetime (<25 ps) renders them potential energy sinks able to compete with the reaction centers and drastically undermine light-harvesting efficiency. Exploration of the orientational phase-space revealed that the placement of central carotenoids minimizes their interaction with the nearest chlorophylls in the plant antenna complexes LHCII, CP26, CP29 and LHCI. At the same time we show that this interaction is highly sensitive to structural perturbations, which has a profound effect on the overall lifetime of the complex. This links the protein dynamics to the light-harvesting regulation in plants by the carotenoids.

/pdf/fine-control-of-chlorophyll-carotenoid-interactions-defines-5afv9n77kx.pdf

Fine control of chlorophyll-carotenoid interactions defines the functionality of light-harvesting proteins in plants

CHARMM is an academic research program used widely for macromolecular mechanics and dynamicswith versatile analysis and manipulation tools of atomic coordinates and dynamics trajectories. CHARMM-GUI,http://www.charmm-gui.org, has been developed to provide a web-based graphical user interface to generate variousinput ﬁles and molecular systems to facilitate and standardize the usage of common and advanced simulation techni-ques in CHARMM. The web environment provides an ideal platform to build and validate a molecular model sys-tem in an interactive fashion such that, if a problem is found through visual inspection, one can go back to the pre-vious setup and regenerate the whole system again. In this article, we describe the currently available functionalmodules of CHARMM-GUI Input Generator that form a basis for the advanced simulation techniques. Future direc-tions of the CHARMM-GUI development project are also discussed brieﬂy together with other features in theCHARMM-GUI website, such as Archive and Movie Gallery.q 2008 Wiley Periodicals, Inc. J Comput Chem 29: 1859–1865, 2008Key words: molecular dynamics; Poisson-Boltzmann; electrostatic potential; membrane; visualization; explicit sol-vent; implicit solvent; MarvinSpace

Wonpil Im

Papers

Software News and Updates CHARMM-GUI: A Web-Based Graphical User Interface for CHARMM