Deciphering collaborative sidechain motions in proteins during molecular dynamics simulations

Taddese, Bruck; Garnier, Antoine; Abdi, Hervé; Henrion, Didier; Chabbert, Marie

doi:10.1038/s41598-020-72766-1

Cited by 8 publications

(10 citation statements)

References 82 publications

(275 reference statements)

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“…The rotamerization of N3.35 from the inward to the outward orientation was observed in several AT2h trajectories (Table III). The outward orientation favors sodium release and subsequent activation [42]. Noteworthy, in one of these trajectories, we observed a steric clash between W6.48 and M3.36, just before the N3.35 outward motion, suggesting that the presence of a methionine at position 3.36 might favor the rotamerization of N3.35.…”

Section: Discussionmentioning

confidence: 70%

Molecular evolution of the Angiotensin II receptors AT1 and AT2: Specificity of the sodium binding site in amniota

Tiss

Benboubaker

Henrion

et al. 2021

Preprint

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In vertebrates, the octopeptide angiotensin II (AngII) is an important in vivo regulator of the cardiovascular system. It acts mainly through two G protein-coupled receptors, AT1 and AT2. To better understand the interplay between these receptors throughout the evolution of the renin-angiotensin system (RAS), we combined a phylogenetic study to electrostatics computations and molecular dynamics (MD) simulations of AT1 and AT2 receptors from different species. The phylogenetic analysis reveals a mirror evolution of AT1 and AT2 that are both split in two clades, separating fish from terrestrian receptors. It also indicates that the unusual allosteric sodium binding site of human AT1 is specific of amniota. Other AT1 and AT2 receptors display a canonical sodium binding site with a serine at position 7.46 (Ballesteros numbering). Electrostatics computations and MD simulations support maintained sodium binding to human AT1 with ingress from the extracellular side. Comparison of the sodium binding modes in AT1 and AT2 from humans and eels indicates that the allosteric control by sodium in both AT1 and AT2 evolved during the transition from an aqueous to a terrestrial environment. The unusual S7.46N mutation in amniota AT1 is mirrored by a L3.36M mutation in amniota AT2. The S7.46N mutation increases the specificity of AT1 for AngII relative to Ang derivatives, whereas the L3.36M mutation might have the opposite effect on AT2. Both mutations should contribute to the split of the renin-angiotensin system into the classical (AngII/AT1) and counter-regulatory (Ang1-7/AT2, Mas) arms in amniota.

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Section: Discussionmentioning

confidence: 70%

Molecular evolution of the Angiotensin II receptors AT1 and AT2: Specificity of the sodium binding site in amniota

Tiss

Benboubaker

Henrion

et al. 2021

Preprint

Self Cite

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“…6 ), which is essential for regulating the interaction between S1 and ACE2. Secondly, the comparative analysis was performed by overlapping the backbone angles ( ϕ ; ψ ) of all three interacting residues Y449, N487, and T500 in S1 [ 5 ], since torsional angle among amino acids is essential for maintaining the structural integrity of a protein system [ 77 ]. Comparing the change in torsional backbone angle of S1 upon interacting with ACE2p and DS9 peptide could effectively validate the ability of DS9 to alter the structural integrity of S1’s pathogenic conformation that can be observed from S1-ACE2p’s interaction.…”

Section: Resultsmentioning

confidence: 99%

Probing the competitive inhibitor efficacy of frog-skin alpha helical AMPs identified against ACE2 binding to SARS-CoV-2 S1 spike protein as therapeutic scaffold to prevent COVID-19

et al. 2022

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In COVID-19 infection, the SARS-CoV-2 spike protein S1 interacts to the ACE2 receptor of human host, instigating the viral infection. To examine the competitive inhibitor efficacy of broad spectrum alpha helical AMPs extracted from frog skin, a comparative study of intermolecular interactions between viral S1 and AMPs was performed relative to S1-ACE2p interactions. The ACE2 binding region with S1 was extracted as ACE2p from the complex for ease of computation. Surprisingly, the Spike-Dermaseptin-S9 complex had more intermolecular interactions than the other peptide complexes and importantly, the S1-ACE2p complex. We observed how atomic displacements in docked complexes impacted structural integrity of a receptor-binding domain in S1 through conformational sampling analysis. Notably, this geometry-based sampling approach confers the robust interactions that endure in S1-Dermaseptin-S9 complex, demonstrating its conformational transition. Additionally, QM calculations revealed that the global hardness to resist chemical perturbations was found more in Dermaseptin-S9 compared to ACE2p. Moreover, the conventional MD through PCA and the torsional angle analyses indicated that Dermaseptin-S9 altered the conformations of S1 considerably. Our analysis further revealed the high structural stability of S1-Dermaseptin-S9 complex and particularly, the trajectory analysis of the secondary structural elements established the alpha helical conformations to be retained in S1-Dermaseptin-S9 complex, as substantiated by SMD results. In conclusion, the functional dynamics proved to be significant for viral Spike S1 and Dermaseptin-S9 peptide when compared to ACE2p complex. Hence, Dermaseptin-S9 peptide inhibitor could be a strong candidate for therapeutic scaffold to prevent infection of SARS-CoV-2. Supplementary Information The online version contains supplementary material available at 10.1007/s00894-022-05117-8.

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“…To summarize the H-bonding pattern of N3.35 observed in the AT1 and AT2 receptors, the inward orientation of N3.35 was always stabilized by H-bond interactions, although at various extents. Thus, in each of the receptors, the collapse of these H-bonds upon the outward rotamerization of N3.35 should destabilize the receptor structure and favour activation, as observed for CXCR4 [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Evolutionary information helps understand distinctive features of the angiotensin II receptors AT1 and AT2 in amniota

et al. 2022

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In vertebrates, the octopeptide angiotensin II (AngII) is an important in vivo regulator of the cardiovascular system. It acts mainly through two G protein-coupled receptors, AT1 and AT2. To better understand distinctive features of these receptors, we carried out a phylogenetic analysis that revealed a mirror evolution of AT1 and AT2, each one split into two clades, separating fish from terrestrial receptors. It also revealed that hallmark mutations occurred at, or near, the sodium binding site in both AT1 and AT2. Electrostatics computations and molecular dynamics simulations support maintained sodium binding to human AT1 with slow ingress from the extracellular side and an electrostatic component of the binding free energy around -3kT, to be compared to around -2kT for human AT2 and the δ opioid receptor. Comparison of the sodium binding modes in wild type and mutated AT1 and AT2 from humans and eels indicates that the allosteric control by sodium in both AT1 and AT2 evolved during the transition from fish to amniota. The unusual S7.46N mutation in AT1 is mirrored by a L3.36M mutation in AT2. In the presence of sodium, the N7.46 pattern in amniota AT1 stabilizes the inward orientation of N3.35 in the apo receptor, which should contribute to efficient N3.35 driven biased signaling. The M3.36 pattern in amniota AT2 favours the outward orientation of N3.35 and the receptor promiscuity. Both mutations have physiological consequences for the regulation of the renin-angiotensin system.

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Deciphering collaborative sidechain motions in proteins during molecular dynamics simulations

Cited by 8 publications

References 82 publications

Molecular evolution of the Angiotensin II receptors AT1 and AT2: Specificity of the sodium binding site in amniota

Molecular evolution of the Angiotensin II receptors AT1 and AT2: Specificity of the sodium binding site in amniota

Probing the competitive inhibitor efficacy of frog-skin alpha helical AMPs identified against ACE2 binding to SARS-CoV-2 S1 spike protein as therapeutic scaffold to prevent COVID-19

Evolutionary information helps understand distinctive features of the angiotensin II receptors AT1 and AT2 in amniota

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