Computational Saturation Mutagenesis of SARS-CoV-1 Spike Glycoprotein: Stability, Binding Affinity, and Comparison With SARS-CoV-2

Abstract

Severe Acute respiratory syndrome coronavirus (SARS-CoV-1) attaches to the host cell surface to initiate the interaction between the receptor-binding domain (RBD) of its spike glycoprotein (S) and the human Angiotensin-converting enzyme (hACE2) receptor. SARS-CoV-1 mutates frequently because of its RNA genome, which challenges the antiviral development. Here, we per-formed computational saturation mutagenesis of the S protein of SARS-CoV-1 to identify the residues crucial for its functions. We used the structure-based energy calculations to analyze the effects of the missense mutations on the SARS-CoV-1 S stability and the binding affinity with hACE2. The sequence and structure alignment showed similarities between the S proteins of SARS-CoV-1 and SARS-CoV-2. Interestingly, we found that target mutations of S protein amino acids generate similar effects on their stabilities between SARS-CoV-1 and SARS-CoV-2. For example, G839W of SARS-CoV-1 corresponds to G857W of SARS-CoV-2, which decrease the stability of their S glycoproteins. The viral mutation analysis of the two different SARS-CoV-1 isolates showed that mutations, T487S and L472P, weakened the S-hACE2 binding of the 2003–2004 SARS-CoV-1 isolate. In addition, the mutations of L472P and F360S destabilized the 2003–2004 viral isolate. We further predicted that many mutations on N-linked glycosylation sites would increase the stability of the S glycoprotein. Our results can be of therapeutic importance in the design of antivirals or vaccines against SARS-CoV-1 and SARS-CoV-2.

Odorant-Binding Protein 3-Oriented Rational Design and Discovery of Novel Jasmonate Derivatives as Potential Aphid-Repellent Agents

“…To further determine the importance of the key residues in the interaction of compound 6b with ApisOBP3, the key residues (TYR27, LYS28, VAL29, TYR102, MET105, LEU108, and ASN109) and three other residues (VAL23, LYS25, and THR103) within the 5 Å range of compound 6b in the binding cavity of ApisOBP3 were selected to perform alanine site-directed mutagenesis. According to previous studies, , a negative value of ΔΔ G led to a more stable binding complex while a positive value of ΔΔ G indicated an unstable complex. Evaluation of the binding free energy change was categorized as follows: highly stabilizing (ΔΔ G <−2.0 kcal/mol), moderately stabilizing (−2.0 ≤ ΔΔ G <−0.5 kcal/mol), neutral (−0.5 ≤ ΔΔ G ≤ 0.5 kcal/ mol), moderately destabilizing (0.5 < ΔΔ G ≤ 2.0 kcal/mol), and highly destabilizing (ΔΔ G > 2.0 kcal/mol).…”

Prediction of the Effects of Missense Mutations on Human Myeloperoxidase Protein Stability Using In Silico Saturation Mutagenesis

“…We showed that the top destabilizing/stabilizing mutations have damaging effects on protein function, except for D264H, which is predicted to have neutral effects ( Table 1 ). In our previous study [ 40 ], we discovered these tools are reliable for analyzing the effects of mutations on protein function.…”

In-silico investigation of systematic missense mutations of middle east respiratory coronavirus spike protein

“…In addition to the aforementioned similarities, there is a similar pattern of predicted effects on the protein stability for MERS-CoV, SARS-CoV-2, and SARS-CoV S proteins. Most of the mutations we generated in the these three full-length S proteins and RBD regions were predicted to have destabilizing effects, ranging from 24 to 37.4% ( Sobitan et al, 2021 ; Teng et al, 2021 ). Mutations predicted to have a neutral effect were also similar between MERS-CoV, SARS-CoV, and SARS-CoV-2 S proteins (25.4–30%).…”

“…Mutations predicted to have a neutral effect were also similar between MERS-CoV, SARS-CoV, and SARS-CoV-2 S proteins (25.4–30%). The percentages of stabilizing mutations generated in the three severely pathogenic coronaviruses ranged from 7.4 to 14% ( Sobitan et al, 2021 ; Teng et al, 2021 ). We found a similar distribution of free folding energy predictions for the RBD region and for the full-length S protein of MERS-CoV.…”