Lipid Head Group Parameterization for GROMOS 54A8: A Consistent Approach with Protein Force Field Description.

Irene Marzuoli,Franca Fraternali,Christian Margreitter

doi:10.1021/acs.jctc.9b00509

Irene Marzuoli, Franca Fraternali + Show 1 more

Open Access

https://doi.org/10.1021/acs.jctc.9b00509

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Abstract

Membranes are a crucial component of both bacterial and mammalian cells, being involved in signaling, transport, and compartmentalization. This versatility requires a variety of lipid species to tailor the membrane’s behavior as needed, increasing the complexity of the system. Molecular dynamics simulations have been successfully applied to study model membranes and their interactions with proteins, elucidating some crucial mechanisms at the atomistic detail and thus complementing experimental techniques. An accurate description of the functional interplay of the diverse membrane components crucially depends on the selected parameters that define the adopted force field. A coherent parameterization for lipids and proteins is therefore needed. In this work, we propose and validate new lipid head group parameters for the GROMOS 54A8 force field, making use of recently published parametrizations for key chemical moieties present in lipids. We make use additionally of a new canonical set of partial charges for lipids, chosen to be consistent with the parameterization of soluble molecules such as proteins. We test the derived parameters on five phosphocholine model bilayers, composed of lipid patches four times larger than the ones used in previous studies, and run 500 ns long simulations of each system. Reproduction of experimental data like area per lipid and deuterium order parameters is good and comparable with previous parameterizations, as well as the description of liquid crystal to gel-phase transition. On the other hand, the orientational behavior of the head groups is more realistic for this new parameter set, and this can be crucial in the description of interactions with other polar molecules. For that reason, we tested the interaction of the antimicrobial peptide lactoferricin with two model membranes showing that the new parameters lead to a weaker peptide–membrane binding and give a more realistic outcome in comparing binding to antimicrobial versus mammal membranes.

Highlights

Cellular membranes are key promoters and regulators of many biological processes due to their crucial role in segregating the external world from the organism
The parameters described in this work are shown to reproduce the available experimental target values well while, at the same time, are likely to allow for a better description of lipid−protein interactions, since the head groups are updated to the recent GROMOS force field
We present a reparameterization of a range of phospholipids in the context of the GROMOS force field, taking advantage of recent optimizations reported for key chemical groups in these molecules

Summary

Introduction

Cellular membranes are key promoters and regulators of many biological processes due to their crucial role in segregating the external world from the organism. Lipids are one of the main components and can be present in up to hundreds of different species.[9] In addition, many transmembrane proteins tessellate the cell surface, promoting signaling pathways and influencing the membrane’s structural and mechanical properties.[10,11] Phospholipid bilayers and micelles have been investigated, in particular, as these lipids represent the main components of the eukaryotic and the inner bacterial membranes Both have been modeled selecting specific phospholipids to emulate the appropriate surface charge or to reproduce the human cell membrane fluidity by introducing, for example, cholesterol.[12,13] As these simplified membranes retain the core characteristics of their different biological templates,[14] they can be used to test the membrane interaction with proteins, peptides, antimicrobial molecules, or drugs

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