A steady-state modeling approach for simulation of antimicrobial peptide-cell membrane interaction
Sumana Srinivasan1, Faiza Hanif Waghu2, Susan Idicula-Thomas3
1Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai-400076, India.
Abstract:
Antimicrobial Peptides (AMPs) are host defense molecules that initiate microbial death by binding to the membrane. On membrane binding, AMPs undergo changes in conformation and aggregation state to enable killing action. Depending on the AMP and cell membrane characteristics, the nature of binding can be aggregating or non-aggregating, with high/low cooperativity, at single or multiple sites with high/low affinity leading to a unique killing action that needs to be studied individually. In the present study, a steady-state model that simulates AMP-membrane interaction was developed and was used to predict the mechanism of AMP binding. The predictions obtained from the model were validated with experimentally deciphered values available in literature. The model was further used to predict the mechanism for a set of designed AMPs with high sequence similarity to Myeloid Antimicrobial Peptide (MAP) family. Depending on the predicted mechanism, a unique half saturation constant and steepness of response (Hill coefficient) was obtained which was further validated with available data from literature. The model could reliably predict the mechanism, the half saturation constant and the Hill coefficient values. Further based on the analysis, it was observed that aggregation and oligomerization result in drastic killing action in a short range of peptide concentration owing to high Hill coefficient values. Mechanisms such as monomers binding at multiple sites with/without cooperativity result in antimicrobial activity at low half saturation constant though the killing action may not be steep. Thus, the methodology developed here can be used to develop hypothesis for studying AMP-membrane interaction mechanisms.
Insights
Antimicrobial peptides (AMPs) kill microbes by binding to cell membranes. This study developed a model to predict AMP binding mechanisms, revealing aggregation enhances killing efficiency.
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Antimicrobial peptides (AMPs) are crucial host defense molecules that eliminate microbes via membrane interactions.
- AMPs undergo conformational and aggregation changes upon membrane binding to exert their killing action.
- The specific mechanism of AMP-membrane binding varies based on peptide and membrane characteristics, necessitating individual study.
Purpose of the Study:
- To develop and validate a steady-state model for predicting AMP-membrane interaction mechanisms.
- To utilize the model to predict binding mechanisms for designed AMPs related to the Myeloid Antimicrobial Peptide (MAP) family.
- To correlate predicted mechanisms with key parameters like half-saturation constant and Hill coefficient.
Main Methods:
- Development of a steady-state computational model simulating AMP-membrane interactions.
- Validation of model predictions against experimentally determined values from existing literature.
- Application of the model to predict binding mechanisms and associated parameters for novel AMP designs.
Main Results:
- The model accurately predicted AMP binding mechanisms, half-saturation constants, and Hill coefficients.
- Aggregation and oligomerization were linked to potent antimicrobial activity within narrow concentration ranges, indicated by high Hill coefficients.
- Monomeric binding at multiple sites, with or without cooperativity, resulted in antimicrobial activity at low half-saturation constants but less steep killing.
Conclusions:
- The developed model reliably predicts AMP-membrane interaction mechanisms and key binding parameters.
- The study highlights the significant impact of AMP aggregation and oligomerization on antimicrobial efficacy.
- This computational approach provides a valuable tool for generating hypotheses in AMP-membrane interaction research.
