Development of a Force Field Topology Database for Detergents for Molecular Dynamics Simulations with the Amber Force Fields

Abstract

Membrane proteins (MPs) are amphiphilic in nature. As such, to be manipulated and studied in aqueous solution and to remain biologically active, MPs need to be transferred in a suitable membrane-mimicking environment such as detergent solutions. Unfortunately, there is no systematic way of identifying the ideal detergent for any given MP, as empirical criterions are often used in this undertaking. Thus, a better knowledge of the interactions between MPs and detergents at the molecular level could improve this situation. Following this approach, our work has focused on the molecular dynamics (MD) simulations of MPs in detergent solutions. In contrast to others FFs (such as CHARMM or GROMOS), AMBER does not provide specific parameter/FF library set for detergents. Consequently, studying MPs by MD with the AMBER FF is not straightforward. In this context, we have developed using R.E.D. Server a complex FF Topology DataBase (FFTopDB) (i.e. RESP partial charges embedded in a large set of FF libraries) for an ensemble of ionic and non-ionic detergents compatible with AMBER FF (available at http://q4md-forcefieldtools.org/). Key points of the procedure are the definition of elementary building blocks with well-identified conformations as well as the derivation of reproducible RESP charge values. The FFTopDB contains more than 75 molecular fragments, which can be used to construct ∼70 different detergents. The approach has been validated by performing MD simulations on dodecylphosphocholine (DPC) micelles with the AMBER99SB parameters and compared to results obtained from CHARMM36 and GROMOS53A6 simulations. We find that this combination of parameters reproduces accurately the micelles structural and dynamical properties. Furthermore, DPC micelles have been used to examine the influence of the micellar environment on the structure and localization of transmembrane peptides of a large MP, hMRP1.