Exploring structural dynamics of the MERS-CoV receptor DPP4 and mutant DPP4 receptors

Alaofi, Ahmed L.

doi:10.1080/07391102.2020.1818626

Cited by 10 publications

(17 citation statements)

References 62 publications

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“…The starting coordinates for each MD simulation system were either X-ray structures (i.e., for the WT RBD and N501Y mutants) or the modeled structures for the L452R, S477N, N439K, and E484K mutants. Then, we performed MD simulations following our previous work with minor changes [ 41 , 42 ]. Each system was solvated with TIP3P water [ 43 ] with the minimal distance of 1.0 nm between the solute and the wall of the dodecahedron box.…”

Section: Methodsmentioning

confidence: 99%

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Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

Alaofi

Shahid

2021

Biomolecules

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The receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates the viral–host interaction and is a target for most neutralizing antibodies. Nevertheless, SARS-CoV-2 RBD mutations pose a threat due to their role in host cell entry via the human angiotensin-converting enzyme 2 receptor that might strengthen SARS-CoV-2 infectivity, viral load, or resistance against neutralizing antibodies. To understand the molecular structural link between RBD mutations and infectivity, the top five mutant RBDs (i.e., N501Y, E484K L452R, S477N, and N439K) were selected based on their recorded case numbers. These mutants along with wild-type (WT) RBD were studied through all-atom molecular dynamics (MD) simulations of 100 ns. The principal component analysis and the free energy landscape were used too. Interestingly, N501Y, N439K, and E484K mutations were observed to increase the rigidity in some RBD regions while increasing the flexibility of the receptor-binding motif (RBM) region, suggesting a compensation of the entropy penalty. However, S477N and L452R RBDs were observed to increase the flexibility of the RBM region while maintaining similar flexibility in other RBD regions in comparison to WT RBD. Therefore, both mutations (especially S477N) might destabilize the RBD structure, as loose conformation compactness was observed. The destabilizing effect of S477N RBD was consistent with previous work on S477N mutation. Finally, the free energy landscape results showed that mutations changed WT RBD conformation while local minima were maintained for all mutant RBDs. In conclusion, RBD mutations definitely impact the WT RBD structure and conformation as well as increase the binding affinity to angiotensin-converting enzyme receptor.

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Section: Methodsmentioning

confidence: 99%

“…Pressure coupling was performed using a reference pressure of 1.0 bar and a time constant of 1.0 ps. Finally, a 100-ns-long production MD simulation at a constant temperature of 300 K, maintained by the v-rescale thermostat, was performed [ 41 , 42 , 44 ].…”

Section: Methodsmentioning

confidence: 99%

Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

Alaofi

Shahid

2021

Biomolecules

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“…As mDPP4 P288T mutation had no effect on MERS-CoV cellular permissiveness; therefore, DPP4 residue 288 is not critical on human permissiveness to MERS-CoV and infection outcome [ 36 , 37 ]. Remarkably, a computational study described DPP4 288 residue as critical inferring a significant flexibility on DPP4 protein without disturbing the binding standing conformation of MERS-CoV S1 RBD after docking with DPP4 [ 12 ]. These findings are in accordance with the effect of the sole T288P mutation on DPP4 –MERS-CoV S1 RBD complex stability described in the present study highlighting a narrower DPP4 blade IV by (1.1 Å) gaining an hydrogen bond with DPP4 C339.…”

Section: Discussionmentioning

confidence: 99%

“…Residues 55–497 form the eight-bladed β-propeller domain, and it has a glycosylation-rich region comprising blades II—V while blades VI—VIII are in a cysteine-rich region. Each blade shows a 4-stranded antiparallel β sheet motif, and blade IV has an additional antiparallel sheet (Asp230-Asn263) between strands 3 and 4 of blade IV [ 11 , 12 ]. According to structural analyses, the MERS-CoV spike protein’s receptor binding domain (RBD) mediates viral infections by binding restrictively to blades IV and V of the N-terminal β-propeller domain of the DPP4 receptor [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Each blade shows a 4-stranded antiparallel β sheet motif, and blade IV has an additional antiparallel sheet (Asp230-Asn263) between strands 3 and 4 of blade IV [ 11 , 12 ]. According to structural analyses, the MERS-CoV spike protein’s receptor binding domain (RBD) mediates viral infections by binding restrictively to blades IV and V of the N-terminal β-propeller domain of the DPP4 receptor [ 12 ]. The resolution of full protein crystallographic structure of the DPP4 binding to MERS-CoV S protein complex mediated the identification of 16 amino acids residues in DPP4 receptor binding domain (RBD) interacting directly with MERS-CoV S protein [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Effect of identified non-synonymous mutations in DPP4 receptor binding residues among highly exposed human population in Morocco to MERS-CoV through computational approach

et al. 2021

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Dipeptidyl peptidase 4 (DPP4) has been identified as the main receptor of MERS-CoV facilitating its cellular entry and enhancing its viral replication upon the emergence of this novel coronavirus. DPP4 receptor is highly conserved among many species, but the genetic variability among direct binding residues to MERS-CoV restrained its cellular tropism to humans, camels and bats. The occurrence of natural polymorphisms in human DPP4 binding residues is not well characterized. Therefore, we aimed to assess the presence of potential mutations in DPP4 receptor binding domain (RBD) among a population highly exposed to MERS-CoV in Morocco and predict their effect on DPP4 –MERS-CoV binding affinity through a computational approach. DPP4 synonymous and non-synonymous mutations were identified by sanger sequencing, and their effect were modelled by mutation prediction tools, docking and molecular dynamics (MD) simulation to evaluate structural changes in human DPP4 protein bound to MERS-CoV S1 RBD protein. We identified eight mutations, two synonymous mutations (A291 =, R317 =) and six non-synonymous mutations (N229I, K267E, K267N, T288P, L294V, I295L). Through docking and MD simulation techniques, the chimeric DPP4 –MERS-CoV S1 RBD protein complex models carrying one of the identified non-synonymous mutations sustained a stable binding affinity for the complex that might lead to a robust cellular attachment of MERS-CoV except for the DPP4 N229I mutation. The latter is notable for a loss of binding affinity of DPP4 with MERS-CoV S1 RBD that might affect negatively on cellular entry of the virus. It is important to confirm our molecular modelling prediction with in-vitro studies to acquire a broader overview of the effect of these identified mutations.

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MERS-Coronavirus (MERS)

Zhang

2023

Springer Series in Biophysics

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Exploring structural dynamics of the MERS-CoV receptor DPP4 and mutant DPP4 receptors

Cited by 10 publications

References 62 publications

Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

Effect of identified non-synonymous mutations in DPP4 receptor binding residues among highly exposed human population in Morocco to MERS-CoV through computational approach

MERS-Coronavirus (MERS)

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