Correlation between chemical denaturation and the unfolding energetics of Acanthamoeba actophorin

Thota, Nikhil; Quirk, Stephen; Zhuang, Yi; Stover, Erica R; Lieberman, Raquel L.; Hernandez, Rigoberto

doi:10.1016/j.bpj.2022.11.2941

Cited by 4 publications

(2 citation statements)

References 80 publications

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“…ASMD has been previously benchmarked on neuropeptide Y and its mutants, deca-alanine in vacuum, implicit and explicit solvents, ,, and β-hairpin. , It has also been utilized successfully by several groups to investigate a large number of biophysical phenomena, such as mutagenesis, , host–guest interactions, protein–ligand interactions, and dissociation mechanisms …”

Section: Methodsmentioning

confidence: 99%

Tertiary Plasticity Drives the Efficiency of Enterocin 7B Interactions with Lipid Membranes

Zhuang,

Quirk,

Stover

et al. 2024

J. Phys. Chem. B

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The ability of antimicrobial peptides to efficiently kill their bacterial targets depends on the efficiency of their binding to the microbial membrane. In the case of enterocins, there is a three-part interaction: initial binding, unpacking of helices on the membrane surface, and permeation of the lipid bilayer. Helical unpacking is driven by disruption of the peptide hydrophobic core when in contact with membranes. Enterocin 7B is a leaderless enterocin antimicrobial peptide produced from Enterococcus faecalis that functions alone, or with its cognate partner enterocin 7A, to efficiently kill a wide variety of Gram-stain positive bacteria. To better characterize the role that tertiary structural plasticity plays in the ability of enterocin 7B to interact with the membranes, a series of arginine single-site mutants were constructed that destabilize the hydrophobic core to varying degrees. A series of experimental measures of structure, stability, and function, including CD spectra, far UV CD melting profiles, minimal inhibitory concentrations analysis, and release kinetics of calcein, show that decreased stabilization of the hydrophobic core is correlated with increased efficiency of a peptide to permeate membranes and in killing bacteria. Finally, using the computational technique of adaptive steered molecular dynamics, we found that the atomistic/energetic landscape of peptide mechanical unfolding leads to free energy differences between the wild type and its mutants, whose trends correlate well with our experiment.

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Section: Methodsmentioning

confidence: 99%

Tertiary Plasticity Drives the Efficiency of Enterocin 7B Interactions with Lipid Membranes

Zhuang,

Quirk,

Stover

et al. 2024

J. Phys. Chem. B

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“…In this method, solvation box size was adjusted between the ASMD stages, hence requiring fewer solvent molecules in the initial stages of the helix−coil transition of polyalanine peptide test system, thereby reducing computational resources at the cost of little numerical errors. In another work by Thota et al, 29 a telescoping solvation box with ASMD was applied to obtain the unfolding PMF of bacterial protein actophorin to explain the increased thermal stability of mutated proteins when compared to the wild type.…”

Section: Introductionmentioning

confidence: 99%

Telescoping-Solvation-Box Protocol-Based Umbrella Sampling Method for Potential Mean Force Estimation

Srivastava,

Patra

2023

J. Chem. Inf. Model.

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Previously, it was shown that the telescoping box scheme, in combination with adaptive steered molecule dynamics (ASMD), can be used to estimate the potential of mean force (PMF) with a decrease in computational cost associated with large solvation boxes. Since ASMD reduces to umbrella sampling (US) in the limit of infinitely slow pulling velocity, a hypothesis was made that the telescoping box scheme can be extended to include the US method. The hypothesis was tested using the unfolding pathway of a polyalanine peptide in a water box and translocation of α-tocopherol through the human membrane. Two different approaches were tried: telescoping US (TELUS), in which the number of solvent molecules was linearly coupled to the reaction coordinate, and Block-TELUS, which was a compromise between the fixed solvation box of the US and the window-wise variable solvation box of TELUS. In the case of polyalanine peptide in a water box, both approaches gave overlapping potential of mean force (PMF) concerning the benchmark US-PMF. Window-wise comparison of properties like root-mean-square inner product, Ramachandran plot, α-helix content, and hydrogen bond formation was used to verify that both approaches captured the same dynamics as the US method. Applying the Block-TELUS protocol in the system with diffusing α-tocopherol through the bilayer resulted in overlapping PMF to its US benchmark. A comparison between the window-wise orientation of the chromanol headgroup also produced almost identical results. This study concluded that with the careful application of telescoping solvation boxes, a less computationally expensive US could be performed for systems where the effect of distant solvent molecules on the configurational space sampled in the window depends on the value of the reaction coordinate.

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Biophysics at the dawn of exascale computers

Singharoy

Pérez

Chipot

2023

Biophysical Journal

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Correlation between chemical denaturation and the unfolding energetics of Acanthamoeba actophorin

Cited by 4 publications

References 80 publications

Tertiary Plasticity Drives the Efficiency of Enterocin 7B Interactions with Lipid Membranes

Tertiary Plasticity Drives the Efficiency of Enterocin 7B Interactions with Lipid Membranes

Telescoping-Solvation-Box Protocol-Based Umbrella Sampling Method for Potential Mean Force Estimation

Biophysics at the dawn of exascale computers

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