Molecular dynamics methods to predict peptide locations in membranes: LAH4 as a stringent test case

Abstract

Determining the structure of membrane-active peptides inside lipid bilayers is essential to understand their mechanism of action. Molecular dynamics simulations can easily provide atomistic details, but need experimental validation. We assessed the reliability of self-assembling (or "minimum-bias") and potential of mean force (PMF) approaches, using all-atom (AA) and coarse-grained (CG) force-fields. The LAH4 peptide was selected as a stringent test case, since it is known to attain different orientations depending on the protonation state of its four histidine residues. In all simulations the histidine side-chains inserted in the membrane when neutral, while they interacted with phospholipid headgroups in their charged state. This led to transmembrane orientations for neutral-His LAH4 in all minimum-bias AA simulations and in most CG trajectories. By contrast, the charged-His peptide stabilized membrane defects in AA simulations, whereas it was located at the membrane surface in some CG trajectories, and interacted with both lipid leaflets in others. This behavior is consistent with the higher antimicrobial activity and membrane-permeabilizing behavior of the charged-His LAH4. In addition, good agreement with solid-state NMR orientational data was observed in AA simulations. PMF calculations correctly predicted a higher membrane affinity for the neutral-His peptide. Interestingly, the structures and relative populations of PMF local free-energy minima corresponded to those determined in the less computationally demanding minimum-bias simulations. These data provide an indication about the possible membrane-perturbation mechanism of the charged-His LAH4 peptide: by interacting with lipid headgroups of both leaflets through its cationic side-chains, it could favor membrane defects and facilitate translocation across the bilayer.

Shedding light on the puzzle of drug-membrane interactions: Experimental techniques and molecular dynamics simulations

“…These models are simplistic and, consequently, they have some limitations, and it is necessary to evaluate whether the selected model fits the purpose of the simulation [86]. However, these models have been used to evaluate drug-membrane interactions, such as volatile anaesthetics [89], antiparasitic drugs [90] and antimicrobial peptides [91][92][93][94][95][96][97][98]. Bereau and Kremer (2015) showed that MD simulations with coarse-grained models can lead to free energy profiles that are similar to those obtained by allatom simulations [99].…”

Attack on Single Escherichia Coli Spheroplasts by Antimicrobial Peptides

“…Chemistry, University of Wisconsin Madison, Madison, WI, USA. Ongoing biophysical and structural investigations will be reported which aim to understand these activities at atomic resolution (5)(6)(7)(8). Apart from tracking membrane permeabilization caused by AMPs, we also observe the effect of AMPs on intracellular components such as the nucleoid and the ribosome.…”

A peptide from human β thymosin as a platform for the development of new anti-biofilm agents for Staphylococcus spp. and Pseudomonas aeruginosa

“…A more efficient protocol was proposed in 2007 by Esteban- Martín and Salgado (2007), by which unordered lipids are allowed to self-organize in the presence of AMP. This strategy has recently led to successful results (Farrotti et al 2015;Khatami et al 2014;Wang et al 2013). …”