Capturing Choline-Aromatics Cation-π Interactions in the MARTINI Force Field.

Hanif M Khan,Sebastian Thallmair,Nathalie Reuter,Siewert J Marrink,Paulo C T Souza,Jonathan Barnoud,Alex H De Vries

doi:10.1021/acs.jctc.9b01194

Hanif M Khan, Sebastian Thallmair + Show 5 more

Open Access

https://doi.org/10.1021/acs.jctc.9b01194

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Abstract

Cation−π interactions play an important role in biomolecular recognition, including interactions between membrane phosphatidylcholine lipids and aromatic amino acids of peripheral proteins. While molecular mechanics coarse grain (CG) force fields are particularly well suited to simulate membrane proteins in general, they are not parameterized to explicitly reproduce cation−π interactions. We here propose a modification of the polarizable MARTINI coarse grain (CG) model enabling it to model membrane binding events of peripheral proteins whose aromatic amino acid interactions with choline headgroups are crucial for their membrane binding. For this purpose, we first collected and curated a dataset of eight peripheral proteins from different families. We find that the MARTINI CG model expectedly underestimates aromatics–choline interactions and is unable to reproduce membrane binding of the peripheral proteins in our dataset. Adjustments of the relevant interactions in the polarizable MARTINI force field yield significant improvements in the observed binding events. The orientation of each membrane-bound protein is comparable to reference data from all-atom simulations and experimental binding data. We also use negative controls to ensure that choline–aromatics interactions are not overestimated. We finally check that membrane properties, transmembrane proteins, and membrane translocation potential of mean force (PMF) of aromatic amino acid side-chain analogues are not affected by the new parameter set. This new version “MARTINI 2.3P” is a significant improvement over its predecessors and is suitable for modeling membrane proteins including peripheral membrane binding of peptides and proteins.

Highlights

Coarse grain (CG) molecular dynamics (MD) simulations have become increasingly popular in recent years for the modeling of complex and large biomolecular systems.[1]
Our work shows that the proposed force field, coined version 2.3P, can improve the description of the role of interfacial aromatics in peripheral protein binding to membranes, including those reliant on choline−aromatics cation−π interactions
We present a modified version of the polarizable MARTINI 2.2P model where the interaction matrix is adjusted to better account for interactions between aromatic amino acids and PC lipids

Summary

INTRODUCTION

Coarse grain (CG) molecular dynamics (MD) simulations have become increasingly popular in recent years for the modeling of complex and large biomolecular systems.[1]. We test the ability of the currently most accurate version of the MARTINI force field (the polarizable version 2.2P) to model the peripheral binding of proteins whose membrane binding depends on choline−aromatics cation−π interactions and on insertion of aromatic amino acids at the bilayer interface. We choose the Bacillus thuringiensis phosphatidylinositol-specific phospholipase C (BtPI-PLC) because the mechanism by which it binds membranes is well-characterized both computationally and experimentally.[21,25] We show that simulations with the polarizable MARTINI CG model do not capture binding events and suggest modifications of the interaction matrix to improve this This modified matrix is validated on a dataset of eight peripheral proteins, including negative controls. Our work shows that the proposed force field, coined version 2.3P, can improve the description of the role of interfacial aromatics in peripheral protein binding to membranes, including those reliant on choline−aromatics cation−π interactions

MATERIALS AND METHODS

Membrane Translocation Potential of Mean

RESULTS AND DISCUSSION

CONCLUSIONS AND FUTURE PERSPECTIVES

■ ACKNOWLEDGMENTS

■ REFERENCES