Biology subjects

Ching, W.-Y.

Publications and source records attributed to Ching, W.-Y..

5 recordsLinked to original sources

bioRxiv2022

Effect of Delta and Omicron mutations on the RBD-SD1 do-main of the Spike protein in SARS-CoV-2 and the Omicron mutations on RBD-ACE2 interface complex

The receptor-binding domain (RBD) is the essential part in the Spike-protein (S-protein) of SARS-CoV-2 virus that directly binds to the human ACE2 receptor, making it a key target for many vaccines and therapies. Therefore, any mutations at this domain could affect the efficacy of these treatments as well as the viral-cell entry mechanism. We introduce ab initio DFT-based computational study that mainly focuses on two parts: (1) Mutations effects of both Delta and Omicron variants in the RBD-SD1 domain. (2) Impact of Omicron RBD mutations on the structure and properties of the RBD-ACE2 interface system. The in-depth analysis is based on the novel concept of amino acid-amino acid bond pair units (AABPU) that reveal the differences between the Delta and/or Omicron mutations and its corresponding wild-type strain in terms of the role played by non-local amino acid interactions, their 3D shapes and sizes, as well as contribution to hydrogen bonding and partial charge distributions. Our results also show that the interaction of Omicron RBD with ACE2 significantly increased its bonding between amino acids at the interface providing information on the implications of penetration of S-protein into ACE2, and thus offering a possible explanation for its high infectivity. Our findings enable us to present in more conspicuous atomic level detail the effect of specific mutations that may help in predicting and/or mitigating the next variant of concern.

biochemistry↗

bioRxiv2022

Atomic-scale Quantum Chemical Calculation of Omicron Mutations Near Cleavage Sites of the Spike Protein

The attachment of the Spike-protein in SARS-CoV-2 to host cells and the initiation of viral invasion are two critical processes in the viral infection and transmission processes in which the presence of unique furin (S1/S2) and TMPRSS2 (S2) cleavage sites play a pivotal role. In this study, we provide detailed analysis of the impact of the BA.1 Omicron variant mutations, vicinal to these two cleavage sites using a novel computational method based on Amino acid - amino acid bond pair unit (AABPU), a specific protein structural unit in 3D as a proxy for quantifying the atomic interaction. We have identified several key features related to the electronic structure as well as bonding of the Omicron mutations near the cleavage sites that significantly increase the size of the relevant AABPUs and the fraction of the positive partial charge. These results of the ultra-large-scale quantum calculations enable us to conjecture on the biological role of Omicron mutations and their specific effects on cleavage sites, as well as identify the principles that can be of some value in analyzing other new variants or subvariants.

biophysics↗

bioRxiv2022

Binding Interactions between RBD of Spike-Protein and Human ACE2 in Omicron variant

Emergence of new SARS-CoV-2 Omicron VOC (OV) has exacerbated the COVID-19 pandemic due to a large number of mutations in the spike-protein, particularly in the receptor-binding domain (RBD), resulting in highly contagious and/or vaccine-resistant strain. Herein, we present a systematic analysis based on detailed molecular dynamics (MD) simulations in order to understand how the OV RBD mutations affect the ACE2 binding. We show that the OV RBD binds to ACE2 more efficiently and tightly due predominantly to strong electrostatic interactions, thereby promoting increased infectivity and transmissibility compared to other strains. Some of OV RBD mutations are predicted to affect the antibody neutralization either through their role in the S-protein conformational changes, such as S371L, S373P, and S375F, or through changing its surface charge distribution, such as G339D, N440K, T478K, and E484A. Other mutations, such as K417N, G446S, and Y505H, decrease the ACE2 binding, whereas S447N, Q493R, G496S, Q498R, and N501Y tend to increase it. TOC GRAPHICS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/480009v1_ufig1.gif" ALT="Figure 1"> View larger version (102K): org.highwire.dtl.DTLVardef@88f654org.highwire.dtl.DTLVardef@1e42d14org.highwire.dtl.DTLVardef@14b7d04org.highwire.dtl.DTLVardef@fca7d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

Mutations of Omicron variant at the interface of the receptor domain motif and human angiotensin-converting enzyme-2

The most recent Omicron variant of SARS-CoV-2 has caused global concern and anxiety. The only thing certain about this strain, with large number of mutations in the spike protein, is that it spreads quickly, seems to evade immune defense and mitigates the benefits of existing vaccines. Based on the ultra-large-scale ab initio computational modeling of the receptor binding motif (RBM) and human angiotensin-converting enzyme-2 (ACE2) interface we provide the details of the effect of Omicron mutations at the fundamental atomic scale level. In-depth analysis anchored in the novel concept of amino acid-amino acid bond pair units (AABPU), indicates that mutations in the Omicron variant are connected with (i) significant changes in the shape and structure of AABPU components, together with (ii) significant increase in the positive partial charge which facilitates the interaction with ACE2. The calculated bond order, based on AABPU, reveals that the Omicron mutations increase the binding strength of RBM to ACE2. Our findings correlate with and are instrumental to explain the current observations and can contribute to the prediction of next potential new variant of concern.

biophysics↗

bioRxiv2021

Delta variant with P681R critical mutation revealed by ultra-large atomic-scale ab initio simulation: Implications for the fundamentals of biomolecular interactions

SARS-CoV-2 Delta variant is emerging as a globally dominant strain. Its rapid spread and high infection rate are attributed to a mutation in the spike protein of SARS-CoV-2 allowing the virus to invade human cells much faster and with increased efficiency. Particularly, an especially dangerous mutation P681R close to the furin cleavage site has been identified as responsible for increasing the infection rate. Together with the earlier reported mutation D614G in the same domain, it offers an excellent instance to investigate the nature of mutations and how they affect the interatomic interactions in the spike protein. Here, using ultra large-scale ab initio computational modeling, we study the P681R and D614G mutations in the SD2-FP domain including the effect of double mutation and compare the results with the wild type. We have recently developed a method of calculating the amino acid-amino acid bond pairs (AABP) to quantitatively characterize the details of the interatomic interactions, enabling us to explain the nature of mutation at the atomic resolution. Our most significant find is that the mutations reduce the AABP value, implying a reduced bonding cohesion between interacting residues and increasing the flexibility of these amino acids to cause the damage. The possibility of using this unique mutation quantifiers in a machine learning protocol could lead to the prediction of emerging mutations.

biochemistry↗