New CHARMM force field parameters for dehydrated amino acid residues, the key to lantibiotic molecular dynamics simulations

Turpin, Eleanor R.; Mulholland, Sam; Teale, Andrew M.; Bonev, Boyan B.; Hirst, Jonathan D.

doi:10.1039/c4ra09897h

Cited by 16 publications

(24 citation statements)

References 64 publications

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“…Hence, we have to rely on modifications such as the ones proposed by Turpin et. al 10 and de Miguel et. al.…”

Section: Effect Of Force Field On Structural Properties and Solubilitmentioning

confidence: 88%

“…Two sets of CHARMM compatible parameters have been proposed for the dehydroamino acids and the thio-ether bridges by Turpin et. al 10 and de Miguel et. al; 11 however, solubility predictions based on these models were never checked and validated.…”

Section: Introductionmentioning

confidence: 88%

“…The antimicrobial activity of nisin relies on two modes: "Lipid II trapping" and "Pore formation". The first mode is due to the N-terminal residues (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) binding to the pyrophosphate moiety of lipid II, 4 which carries the peptidoglycan unit, thus competing with the biosynthesis of the cell wall. At the same time, the C-terminus of nisin enables the formation of pores in the cell membrane, thus causing cell leakage resulting in cell death.…”

Section: Introductionmentioning

confidence: 99%

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Altering the solubility of the antibiotic candidate Nisin – a computational study

Pandey

Hansmann

Wang

2020

Preprint

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The growing bacterial resistance to available antibiotics makes it necessary to look for new drug candidates. An example is a lanthionine containing nisin, which has a broad spectrum of antimicrobial activity. While nisin is widely utilized as a food preservative, its poor solubility and low stability at physiological pH hinder its use as an antibiotic. As the solubility of nisin is controlled by the residues of the hinge region, we have performed molecular dynamics simulations of various mutants and studied their effects on nisin's solubility. These simulations are complicated by the presence of two uncommon residues (dehydroalanine and dehydrobutyrine) in the peptide. The primary goal of the present study is to derive rules for designing new mutants that will be more soluble at physiological pH and, therefore, may serve as a basis for the future antibiotic design. Another aim of our study is to evaluate whether existing force fields can model the solubility of these amino acids accurately, in order to motivate further developments of force fields to account for solubility information.

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“…Hence, we have to rely on modifications such as the ones proposed by Turpin et. al 10 and de Miguel et. al.…”

Section: Effect Of Force Field On Structural Properties and Solubilitmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Altering the solubility of the antibiotic candidate Nisin – a computational study

Pandey

Hansmann

Wang

2020

Preprint

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“…Very recently, new CHARMM force field parameters for Dhb and Dha were reported by Turpin et al [29]. In their work, the force field parametrization was performed using a well-established procedure based on the Paramchem interface (www.paramchem.org).…”

Section: Methodsmentioning

confidence: 99%

Structure, dynamics and kinetics of two-component Lantibiotic Lichenicidin

et al. 2017

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Two variants of the two-component Lantibiotic Lichenicidin, produced by the strains B. Licheniformis VK21 and I89 (Lchα/ Lchβ and Bliα/ Bliβ peptides, respectively) have been investigated by means of 2 μs-long all-atom molecular dynamics simulations combined with Markov State Models. This rigorous statistical analysis enabled to evaluate the dynamic and kinetic properties of the aforementioned systems which are not accessible via experimental techniques. The structural flexibility characteristic of these small peptides is understood by a delicate equilibrium between random coil, α-helices and β-sheet structures. The undergoing secondary structure transitions from an α-helix to a β-sheet observed for Lchα and Lchβ peptides, were not present in the Bliα component and provide new insights to understand their mechanism of action.

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“…Chugunov et al 26 have made an extensive analysis of the behavior of lipid-II in a membrane using MD simulations, identifying distinct conformations of the lipid-II tail in the bilayer and an induced amphiphilic ‘landing terrain’ pattern on a model bacterial membrane surface that is not seen in a reference membrane. More recently we have developed CHARMM empirical force-field parameters for the unusual dehydrated amino acids present in lantibiotics 27 . MD simulations of nisin in an aqueous environment interacting with a phospholipid bilayer were conducted and the conformation and dynamics of the peptide agreed with solid state and solution NMR 20 .…”

mentioning

confidence: 99%

Docking and molecular dynamics simulations of the ternary complex nisin2:lipid II

Mulholland

Turpin

Bonev

et al. 2016

Sci Rep

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Lanthionine antibiotics are an important class of naturally-occurring antimicrobial peptides. The best-known, nisin, is a commercial food preservative. However, structural and mechanistic details on nisin-lipid II membrane complexes are currently lacking. Recently, we have developed empirical force-field parameters to model lantibiotics. Docking and molecular dynamics (MD) simulations have been used to study the nisin2:lipid II complex in bacterial membranes, which has been put forward as the building block of nisin/lipid II binary membrane pores. An Ile1Trp mutation of the N-terminus of nisin has been modelled and docked onto lipid II models; the computed binding affinity increased compared to wild-type. Wild-type nisin was also docked onto three different lipid II structures and a stable 2:1 nisin:lipid II complex formed. This complex was inserted into a membrane. Six independent MD simulations revealed key interactions in the complex, specifically the N-terminal engagement of nisin with lipid II at the pyrophosphate and C-terminus of the pentapeptide chain. Nisin2 inserts into the membrane and we propose this as the first step in pore formation, mediated by the nisin N-terminus–lipid II pentapeptide hydrogen bond. The lipid II undecaprenyl chain adopted different conformations in the presence of nisin, which may also have implications for pore formation.

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New CHARMM force field parameters for dehydrated amino acid residues, the key to lantibiotic molecular dynamics simulations

Cited by 16 publications

References 64 publications

Altering the solubility of the antibiotic candidate Nisin – a computational study

Altering the solubility of the antibiotic candidate Nisin – a computational study

Structure, dynamics and kinetics of two-component Lantibiotic Lichenicidin

Docking and molecular dynamics simulations of the ternary complex nisin2:lipid II

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