Tripleurin XIIc: Peptide Folding Dynamics in Aqueous and Hydrophobic Environment Mimic Using Accelerated Molecular Dynamics

Abstract

Peptaibols are a special class of fungal peptides with an acetylated N-terminus and a C-terminal 1,2-amino alcohol along with non-standard amino acid residues. New peptaibols named tripleurins were recently identified from a strain of the filamentous fungal species Trichoderma pleuroti, which is known to cause green mould disease on cultivated oyster mushrooms. To understand the mode of action of these peptaibols, the three-dimensional structure of tripleurin (TPN) XIIc, an 18-mer peptide, was elucidated using an enhanced sampling method, accelerated MD, in water and chloroform solvents. Non-standard residues were parameterized by the Restrained Electrostatic Potential (RESP) charge fitting method. The dihedral distribution indicated towards a right-handed helical formation for TPN XIIc in both solvents. Dihedral angle based principal component analysis revealed a propensity for a slightly bent, helical folded conformation in water solvent, while two distinct conformations were revealed in chloroform: One that folds into highly bent helical structure that resembles a beta-hairpin and another with an almost straight peptide backbone appearing as a rare energy barrier crossing event. The hinge-like movement of the terminals was also observed and is speculated to be functionally relevant. The convergence and efficient sampling is addressed using Cartesian PCA and Kullback-Leibler divergence methods.

Accelerated Molecular Dynamics Applied to the Peptaibol Folding Problem

“…It supports the idea of a dynamic equilibrium between the two conformations in line with previous studies [39]. Similar results were also obtained in our previous studies with other fungal peptaibols for example, trikoningin KA V [41], the energy minimum conformation of tripleurin XIIc obtained in the hydrophobic solvent chloroform [36], paracelsins B and H, and the newly discovered brevicelsin I and IV molecules [42]. This movement along the backbone from bent to linear conformation is the largest scale of motion as described by the first mode calculated through normal mode wizard (Supplementary Video 1).…”

“…The rapidly decreasing slope of KLD vs time of any two trajectories indicates the reduction in divergence between sampled conformations. We chose the KLD value of 0.025 as cutoff for convergence based on a previous study [36]. As evident from Figure 3B, convergence for Mode 1 for all four trajectories, except Sim 2, is obtained only after 700 ns.…”

Structural Diversity and Bioactivities of Peptaibol Compounds From the Longibrachiatum Clade of the Filamentous Fungal Genus Trichoderma

“…Calculation of the partial charges for the non-standard residues Aib and Pheol and the preparation of unfolded conformations of four selected peptaibols in water were carried out as described by Tyagi et al (2019). The Leu and Val positions in brevicelsin sequences were predicted based on their positionally isomeric 20-residue paracelsin counterparts.…”

“…Computational molecular dynamics-based simulation is a popular technique for investigating a molecule's dynamic behavior and predicting its three-dimensional structure. Peptaibols like trichobrachins (Násztor et al, 2013), harzianins (Putzu et al, 2017), alamethicin (Leitgeb et al, 2007; Kredics et al, 2013), tripleurin (Tyagi et al, 2019), and others have been investigated using such techniques. Knowledge about the structure of peptaibols might also facilitate the design of bioactive peptides for future applications.…”

Changes in Peptaibol Production of Trichoderma Species during In Vitro Antagonistic Interactions with Fungal Plant Pathogens

“…Trichotoxins belong to the sub-family 1 of peptaibols. The high number of Aib residues in the sequence is evidence of α-helical structure [65]. It was noted in the literature that one Gln residue near the middle of the sequence (frequently in position 6 or 7) and another one in the C-terminal play a conducting role in the pore lumen [66].…”