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Conformation and binding of 12 Microcystin (MC) congeners to PPP1 using molecular dynamics simulations: A potential
Sabrina Jaeger-Honz1, Raymund Hackett1, Regina Fotler2
1Department of Informatics and Information Science, University of Konstanz, Germany.
Abstract:
Microcystins (MCs) occur frequently during cyanobacterial blooms worldwide, representing a group of currently about 300 known MC congeners, which are structurally highly similar. Human exposure to MCs via contaminated water, food or dietary supplements can lead to severe intoxications with ensuing high morbidity and in some cases mortality. Currently, one MC congener (MC-LR) is almost exclusively considered for risk assessment (RA) by the WHO. Many MC congeners co-occur during bloom events, of which MC-LR is not the most toxic. Indeed, MC congeners differ dramatically in their inherent toxicity, consequently raising question about the reliability of the WHO RA and the derived guidance values. Molecular dynamics (MD) simulation can aid in understanding differences in toxicity, as experimental validation for all known MC congeners is not feasible. Therefore, we present MD simulations of a total of twelve MC congeners, of which eight MC congeners were simulated for the first time. We show that depending on their structure and toxicity class, MCs adapt to different backbone conformations. These backbone conformations are specific to certain MC congeners and can change or shift to other conformations upon binding to PPP1, affecting the stability of the binding. Analysis of the interactions with PPP1 demonstrated that there are frequently occurring patterns for individual MC congeners, and that published PPP interactions could be reproduced. In addition, common but also unique patterns were found for individual MC congeners, suggesting differences in binding behaviour. The MD simulations presented here therefore enhance our understanding of MC congener-specific differences and demonstrated that congener-specific investigations are prerequisite for allowing characterisation of yet untested or even unknown MC congeners, thereby allowing for a novel potential approach in support of an improved RA of microcystins in humans.
Insights
Molecular dynamics simulations reveal distinct microcystin (MC) backbone conformations influencing toxicity. Congener-specific analysis is crucial for accurate human risk assessment of these cyanobacterial toxins.
Area of Science:
- Environmental toxicology
- Computational chemistry
- Biochemistry
Background:
- Microcystins (MCs) are cyanobacterial toxins with diverse congeners, posing health risks through contaminated water and food.
- Current risk assessment primarily focuses on MC-LR, overlooking the varying toxicity of other MC congeners.
- Experimental toxicity testing for all ~300 MC congeners is impractical.
Purpose of the Study:
- To investigate congener-specific differences in microcystin toxicity using molecular dynamics (MD) simulations.
- To explore how MC structures adapt conformations upon binding to protein phosphatase 1 (PPP1).
- To provide a basis for improved risk assessment of microcystins.
Main Methods:
- Performed MD simulations for twelve MC congeners, including eight novel simulations.
- Analyzed MC backbone conformations and their stability during binding to PPP1.
- Examined interaction patterns between MC congeners and PPP1.
Main Results:
- MC congeners adopt distinct backbone conformations based on their structure and toxicity.
- Conformations can shift upon PPP1 binding, impacting binding stability.
- Identified common and unique interaction patterns between MCs and PPP1, highlighting congener-specific binding behaviors.
Conclusions:
- MD simulations reveal congener-specific conformational adaptations and binding interactions of microcystins.
- These findings underscore the necessity of congener-specific investigations for accurate toxicity evaluation.
- This approach offers a potential method for characterizing untested or unknown MC congeners, improving human risk assessment.
