First-Principles Simulation of Dielectric Function in Biomolecules

Podgornik

et al. 2022

IJMS

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The most recent Omicron variant of SARS-CoV-2 has caused global concern and anxiety. The only thing certain about this strain, with a 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 the 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. We have identified changes in bonding due to mutations in the RBM. 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.

Section: Model Constructionsmentioning

confidence: 99%

Mutations of Omicron Variant at the Interface of the Receptor Domain Motif and Human Angiotensin-Converting Enzyme-2

Podgornik

et al. 2022

IJMS

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“…The results are divided into the following four sections. Section 4.1 and Section 4.2 are standard electronic structures routinely present for the analysis in biomolecular systems [ 31 , 46 , 47 , 48 , 49 , 50 ]. Section 4.2 describes the key data on interatomic interactions between all atoms whose results are used for the main Section 4.3 on the AABP data for the four SD2-FP models (a) to (d) listed in Table S2 .…”

Section: Resultsmentioning

confidence: 99%

Delta Variant with P681R Critical Mutation Revealed by Ultra-Large Atomic-Scale Ab Initio Simulation: Implications for the Fundamentals of Biomolecular Interactions

Rao

et al. 2022

Viruses

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The 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 for the virus to invade human cells much faster and with an increased efficiency. In particular, 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 finding 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.

“…This is followed by using a different DFT method developed in-house, the all-electron orthogonalized linear combination of atomic orbitals (OLCAO) method [ 29 ]. OLCAO method is extremely efficient in probing the electronic structure, partial charge distributions, and interatomic bonding including the hydrogen bonding network and the AA–AA interactions [ 30 , 47 , 67 , 68 , 69 , 70 , 71 ]. These methods are fully described in Supplementary Materials .…”

Section: Methodsmentioning

confidence: 99%

Computational Design of Miniproteins as SARS-CoV-2 Therapeutic Inhibitors

Cheng

et al. 2022

IJMS

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A rational therapeutic strategy is urgently needed for combating SARS-CoV-2 infection. Viral infection initiates when the SARS-CoV-2 receptor-binding domain (RBD) binds to the ACE2 receptor, and thus, inhibiting RBD is a promising therapeutic for blocking viral entry. In this study, the structure of lead antiviral candidate binder (LCB1), which has three alpha-helices (H1, H2, and H3), is used as a template to design and simulate several miniprotein RBD inhibitors. LCB1 undergoes two modifications: structural modification by truncation of the H3 to reduce its size, followed by single and double amino acid substitutions to enhance its binding with RBD. We use molecular dynamics (MD) simulations supported by ab initio density functional theory (DFT) calculations. Complete binding profiles of all miniproteins with RBD have been determined. The MD investigations reveal that the H3 truncation results in a small inhibitor with a −1.5 kcal/mol tighter binding to RBD than original LCB1, while the best miniprotein with higher binding affinity involves D17R or E11V + D17R mutation. DFT calculations provide atomic-scale details on the role of hydrogen bonding and partial charge distribution in stabilizing the minibinder:RBD complex. This study provides insights into general principles for designing potential therapeutics for SARS-CoV-2.