key: cord-0778482-sc6crkkw
authors: Ali, Fedaa; Elserafy, Menattallah; Alkordi, Mohamed H.; Amin, Muhamed
title: ACE2 coding variants in different populations and their potential impact on SARS-CoV-2 binding affinity
date: 2020-08-20
journal: Biochem Biophys Rep
DOI: 10.1016/j.bbrep.2020.100798
sha: 2d14cd1c13358f6a978bc8004414cd91260265f9
doc_id: 778482
cord_uid: sc6crkkw

The susceptibility of different populations to SARS-CoV-2 infection is not yet understood. Here, we combined ACE2 coding variants analysis in different populations and computational chemistry calculations to probe the effects on SARS-CoV-2/ACE2 interaction. ACE2-K26R; which is most frequent in Ashkenazi Jewish population decreased the SARS-CoV-2/ACE2 electrostatic attraction. On the contrary, ACE2-I468V, R219C, K341R, D206G, G211R increased the electrostatic attraction; ordered by binding strength from weakest to strongest. The aforementioned variants are most frequent in East Asian, South Asian, African and African American, European, European and South Asian populations, respectively.

infected patients, specifically patients with hypertension, diabetes mellitus, coronary heart 25 diseases, and cerebrovascular disease that showed increased risk. Whether ACE2 polymorphisms 26 linked to the aforementioned diseases or administration of ACE2 modulating drugs have larger 27 impact on the severity of infection is still a question to be investigated [3] . 28 29 Communications between the pathogen and the host is mainly governed by the different protein-30 protein electrostatic interactions [4] . These proteins need to bind in a specific way for protein-31 protein complexes formation and for the signals to be effectively transmitted. The existence of 32 residues that are involved in energetically favorable interactions at the protein-protein interface 33 leads to enhanced interactions leading to viral-host cells fusion, marking the onset of the 34 infection [2,5]. Therefore, we opted herein to investigate the nature of the interactions at the 35 SARS-CoV-2/ACE2 interface, and how the subtle variations in the structure of ACE2, induced 36 by certain mutations, can alter the binding of SARS-CoV-2 in different populations. This was 37 attempted here by analyzing different ACE2 missense variants that code for ACE2-K26R, 38 structures are defined depending on rotamers and protonation states of the different amino acids. 63

The protein interior is considered as highly polar media with low dielectric constant ( = 4), 64

whereas the solvent (water) is treated as a continuum medium with high dielectric constant 65 ( = 80). 66 67 Initial coordinates are defined according to the X-ray crystal structure of the wild type (WT) 68 human ACE2 with the receptor-binding domain RBD of the S protein of SARS-CoV-2 (PDB ID: 69 6M17) from the protein data bank [2] . The structure of the Neutral amino acid transporter B 0 AT1 70 was removed from the PDB file, as it is far from the SARS-CoV-2/ACE2 binding site. 71

Furthermore, the structure of ACE2 was trimmed by removing residues from P733 to the end of The electrostatic and the van der Waal contribution to the interaction energies of SARS-CoV-108 2/ACE2 were compared between single mutated and WT protein at pH =7 ( Fig. 2A) . In contrary 109 to K26R, most of the mutated structures exhibit a negative shift in the total interaction energy 110 compared to the WT structure (Native) i.e. more electrostatic attraction with the spike protein of 111 SARS-CoV-2. Based on our calculations, G211R mutant is shown to induce the largest increase 112 in the binding energy between SARS-CoV-2 and ACE2, where the binding is more favorable by 113 ~ 7.6 Kcal/mol than the WT. However, the K26R mutant causes a decrease in the binding 114 energies by ~ 2.1 Kcal/mol ( Fig. 2A and B) . reduce the electrostatic attraction between SARS-CoV-2 and ACE2 to 2.59 Kcal/mol lower than 120 that in WT. In addition, the D206G mutant showed similar electrostatic interactions to the WT. 121

However, the R219C, I468V mutants showed significant decrease in the electrostatic attraction 122 to by ~5 Kcal/mol compared to the WT ( Fig. 2A and B ). SARS-CoV-2/ACE2 interface in the 123 WT protein and corresponding mutants is showed to be a dominated by van der Waals 124 interactions, which accounts for more than 60% of the interaction energy. All the mutations 125 except K341R induced an increase in the van der Waals attractions between the ACE2 and the 126 SARS-CoV-2. The largest increase of ~ 8 Kcal/mol is observed for the R219C mutant ( Fig. 2A) . 

Electrostatic aspects of protein-protein interactions

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MCCE2: Improving protein pKa calculations with 208 extensive side chain rotamer sampling

dbSNP: a database of single nucleotide polymorphisms

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Comparative genetic analysis of the novel coronavirus

receptor ACE2 in different populations

The ChinaMAP analytics of 230 deep whole genome sequences in 10,588 individuals

The impact of rare and low-frequency genetic variants 233 in common disease