Search

Treatment of COVID-19 with a soluble version of ACE2 that binds to SARS-CoV-2 virions before they enter host cells is a promising approach, however it needs to be optimized and adapted to emerging viral variants. The computational workflow presented here consists of molecular dynamics simulations for spike RBD-hACE2 binding affinity assessments of multiple spike RBD/hACE2 variants and a novel convolutional neural network architecture working on pairs of voxelized force-fields for efficient search-space reduction. We identified hACE2-Fc K31W and multi-mutation variants as high-affinity candidates, which we validated in vitro with virus neutralization assays. We evaluated binding affinities of these ACE2 variants with the RBDs of Omicron BA.3, Omicron BA.4/BA.5, and Omicron BA.2.75 in silico. In addition, candidates produced in Nicotiana benthamiana, an expression organism for potential large-scale production, showed a 4.6-fold reduction in half-maximal inhibitory concentration (IC50) compared with the same variant produced in CHO cells and an almost six-fold IC50 reduction compared with wild-type hACE2-Fc. [ABSTRACT FROM AUTHOR]

The discovery of hydrogen atoms on the TiO2 surface is crucial for many practical applications, including photocatalytic water splitting. Electronically activating interfacial hydrogen atoms on the TiO2 surface is a common way to control their reactivity. Modulating the potential landscape is another way, but dedicated studies for such an activation are limited. Here we show the single hydrogen atom manipulation, and on-surface facilitated water deprotonation process on a rutile TiO2 (110) surface using low temperature atomic force microscopy and Kelvin probe force spectroscopy. The configuration of the hydrogen atom is manipulated on this surface step by step using the local field. Furthermore, we quantify the force needed to relocate the hydrogen atom on this surface using force spectroscopy and density functional theory. Reliable control of hydrogen atoms provides a new mechanistic insight of the water molecules on a metal oxide surface. Rutile TiO2 is a prominent photocatalyst for overall water splitting, but the on-surface activation of hydrogen atoms is still not fully understood. Here, the authors use atomic force and kelvin probe force microscopy to study the lateral manipulation of hydrogen on a rutile (110) surface. [ABSTRACT FROM AUTHOR]

VP35 of Ebola viruses (EBOVs) is an attractive potential target because of its multifunction. All-atom molecular dynamics (MD) simulations and Molecular Mechanics Generalized Born surface area (MM/GBSA) energy calculations are performed to investigate the single-walled carbon nanotube (SWCNT) as an inhibitor in wild-type (WT) VP35 as well as in three primary mutants (K248A, I295A, and K248A/I295A) through docking the SWCNT in the first basic patch (FBP) of VP35. The SWCNTs of all the four systems effectively bind to the FBP. Interestingly, the sites and orientations of the SWCNT binding to the I295A mutant and K248A/I295A double mutants change significantly to accommodate the variation of the VP35 conformation. Moreover, the VDW can provide the major forces for affinity binding in all four systems. [ABSTRACT FROM AUTHOR]

The Hsp90 (for heat shock protein90) and the Sgt1 (for suppressor of the G2 allele of skp1) are widely distributed in animals, yeast, and plants. The former functions as molecular chaperon activating a series of client proteins, the latter functions as an adaptor protein participating in multiple biological processes such as immunity response through interactions with different protein complexes. In the present study, we have constructed a homology model of Hsp90-Sgt1 complex in rice based on a recently resolved structure from barley and Arabidopsis to explore its binding mechanisms and to understand the detailed interaction profile. A total of 20 ns explicit solvent molecular dynamics simulations combined with MM-GBSA computations and virtual alanine scanning were performed for the modeled complex. In the final structure, three strong salt bridges were found between OsHsp90 and OsSgt1, D217(OsHsp90) - K186(OsSgt1), D218(OsHsp90) - K237(OsSgt1) and K161(OsHsp90) - E239(OsSgt1). Besides, residue Y173 of OsSgt1 played a vital role in the interactions with OsHsp90, the detailed interactions were discussed. These results would help us understand the critical features determining the Hsp90-Sgt1 binding process. [ABSTRACT FROM AUTHOR]