SARS CoV-2 SPIKE GLYCOPROTEIN MUTATIONS AND CHANGES IN PROTEIN STRUCTURE

Akbulut, Ekrem

doi:10.23902/trkjnat.774926

Cited by 4 publications

(3 citation statements)

References 84 publications

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“…In this study, changes in 3CL pro stability and activity caused by mutations in South African isolates were investigated in silico . Mutations can cause changes in the structure and stability of drug target proteins, resulting in changes in substrate and ligand affinity ( Akbulut, 2020 b; Xavier et al, 2021 ). In silico studies have achieved great success in recent years due to their contributions to the design and development of effective drug molecules in a short time, taking these changes into account ( Prabhavathi et al, 2020 ; Das et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Investigation of changes in protein stability and substrate affinity of 3CL-protease of SARS-CoV-2 caused by mutations

Akbulut

2022

Genet. Mol. Biol.

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3CL pro of SARS-CoV-2 is one of the enzymes required for the replication process of the virus responsible for the COVID-19 pandemic. In this study, changes in protein stability and substrate affinity caused by mutations were investigated to stir the development of potent inhibitors. Sequence data of samples were obtained from the NCBI Virus database. Mutation analyses were performed with RDP4 and MegaX. 3CL pro tertiary models were created using Robetta. Molecular docking for peptidomimetic substrate and inhibitor ligand was done with Autodock v4.2 and Haddock v2.4. Protein stability analysis was performed using mCSM stability and DynaMut2. Twenty-four missense mutations in 3CL pro were identified in this study. Changes in the 3CL pro structure induced by the mutations Met49Thr, Leu167Ser, and Val202Ala resulted in significant levels of instability (-2.029,-2.612,-2.177 kcal.mol -1 , respectively). The lowest interaction energy for substrate was -58.7 kcal.mol -1 and -62.6 kcal.mol -1 in wild-type and mutant, respectively. The lowest docking energy for ligand was -6.19 and -9.52 kcal.mol -1 for wild-type and mutant, respectively. This study reports for the first time that mutations cause increased substrate affinity of 3CL pro from SARS-CoV-2. This research provides important data for the development of potent peptidomimetic inhibitors for the treatment of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Investigation of changes in protein stability and substrate affinity of 3CL-protease of SARS-CoV-2 caused by mutations

Akbulut

2022

Genet. Mol. Biol.

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“…A location-based evaluation of mutations is important in terms of the behavior of the virus in the cellular invasion process, the progression of the epidemic, and the specification of treatment options (34,35). The SARS CoV-2 has undergone thousands of mutations since the outbreak began, resulting in significant changes in its genome and protein structure (36,37). These changes manifested as various characteristics such as more virulence, increased affinity for the angiotensin converting enzyme-2 receptor, and faster host transition (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

The Effects of SARS CoV-2 nsp13 Mutations on the Structure and Stability of Helicase in Chinese Isolates

Akbulut¹

2022

ejb

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Objective: Coronavirus Disease 2019 (COVID19) is a viral disease caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2). The high mutation propensity of the SARS CoV-2 genome is one of the biggest threats to the long-term validity of treatment options. Helicases are anti-viral targets because of the vital role they play in the viral life cycle. In this study, changes in the protein structure caused by SARS CoV-2 nsp13 mutations were investigated to contribute to the development of effective antiviral drugs. Materials and Methods:Genome data of 298 individuals located in the China location were examined. The mutant model was built using deep learning algorithms. Model quality assessment was done with QMEAN. Protein stability analyses were performed with DynaMut2 and Cutoff Scanning Matrix stability. Changes in substrate affinity were performed with Haddock v2.4. Results:In this study, twenty-eight mutations in nsp13 were identified (23 sense, 5 missense). The changes in protein structure caused by the five missense mutations (Leu14Phe, Arg15Ser, Arg21Ser, Leu235Phe, Ala454Thr) were modeled. The mutations caused a decrease in the stability of SARS CoV-2 helicase (-0.99, -1.66, -1.15, -0.54, and -0.73 for Leu14Phe, Arg15Ser, Arg21Ser, Leu235Phe, Ala454Thr, respectively). The mutations reduced the helicase's affinity to the substrate. The docking scores for wild-type and mutant helicase were -84.4±1.4 kcal.mol -1 and -71.1±6.7 kcal.mol -1 , respectively. Conclusion:Helicase mutations caused a decrease in the protein stability and nucleic acid affinity of the SARS CoV-2 helicase. The results provide important data on the development of potential antivirals and the effect of mutation on the functions of viral proteins.

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“…More than 12,000 mutations have been identified in the SARS-CoV-2 genome to date. While some of these mutations do not cause any changes in the virulence properties of the virus, some of them may have negative results in many factors ranging from virulence features to treatment sensitivity [11][12][13].…”

Section: Highlightsmentioning

confidence: 99%

Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity

Akbulut

2021

Braz. arch. biol. technol.

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The coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health emergency. The main protease (M pro ) is crucial for the life cycle of coronaviruses. Boceprevir is a potential inhibitor and drug candidate for the M pro of SARS-CoV-2. In this study, changes in the protein structure of the M pro due to mutations in SARS-CoV-2 and the effects of these changes on boceprevir affinity, an important potential therapeutic agent, were investigated. The mutations were analyzed with RDP4 and MegaX. A three-dimensional model of mutant M pro was generated by ProMod3. Qualitative Model Energy Analysis, ProSA, and MolProbity tools were used for structural validation and modeling of the wild-type and mutant M pro proteins. Topological differences of the wild-type and mutant M pro were calculated with the i-Tasser TM-Score. Molecular docking was performed using AutoDock 4.2. Functional dynamic structure models were created with DynOmics. Seven mutations (L89F, K90R, P108S, A191V, T224A, A234V and S254F) were detected in the M pro of SARS-CoV-2. The mutations caused a decrease in the affinity of boceprevir, a potential protease inhibitor. The boceprevir was docked to the active site of M pro , and the binding energies were −10.34 and −9.41 kcal.mol -1 for the wild-type and the mutant, respectively. The Debye-Waller factors calculated by elastic network model analysis were 0.58 and 0.64 Å 2 for the wild-type M pro and mutant M pro , respectively. Mutations in structures that are important drug targets for SARS-CoV-2 may render existing therapeutics ineffective in its treatment.

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SARS CoV-2 SPIKE GLYCOPROTEIN MUTATIONS AND CHANGES IN PROTEIN STRUCTURE

Cited by 4 publications

References 84 publications

Investigation of changes in protein stability and substrate affinity of 3CL-protease of SARS-CoV-2 caused by mutations

Investigation of changes in protein stability and substrate affinity of 3CL-protease of SARS-CoV-2 caused by mutations

The Effects of SARS CoV-2 nsp13 Mutations on the Structure and Stability of Helicase in Chinese Isolates

Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity

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