Molecular dynamics methods to predict peptide locations in membranes: LAH4 as a stringent test case
A Farrotti1, G Bocchinfuso1, A Palleschi1
1Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma "Tor Vergata", 00133, Rome, Italy.
Biochimica Et Biophysica Acta
|December 3, 2014
Summary
Molecular dynamics simulations reveal how peptide protonation affects membrane structure. Charged histidine residues in the LAH4 peptide induce membrane defects, explaining its antimicrobial activity.
Area of Science:
- Biophysics
- Computational Chemistry
- Membrane Biology
Background:
- Understanding membrane-active peptide structure within lipid bilayers is crucial for elucidating their function.
- Molecular dynamics (MD) simulations offer atomistic detail but require experimental validation.
Purpose of the Study:
- To assess the reliability of self-assembling (minimum-bias) and potential of mean force (PMF) simulation approaches for studying peptide-lipid interactions.
- To investigate the influence of histidine protonation state on the orientation and membrane interaction of the LAH4 peptide.
Main Methods:
- Utilized all-atom (AA) and coarse-grained (CG) molecular dynamics force fields.
- Employed minimum-bias and PMF simulation techniques.
- Validated simulation results with solid-state NMR data.
Main Results:
- Neutral histidine residues inserted into the membrane, leading to transmembrane orientations for LAH4.
- Charged histidine residues induced membrane defects in AA simulations and showed varied localization in CG simulations.
- PMF calculations accurately predicted higher membrane affinity for the neutral-His peptide and revealed minima consistent with minimum-bias simulations.
Conclusions:
- Peptide protonation state significantly dictates membrane interaction and orientation.
- The charged-His LAH4 peptide's interaction with lipid headgroups may promote membrane defects and facilitate translocation.
- Minimum-bias simulations provide reliable structural insights comparable to more computationally intensive PMF calculations.
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