posted on 2021-08-16, 16:35authored bySebastian Thallmair, Matti Javanainen, Balázs Fábián, Hector Martinez-Seara, Siewert J. Marrink
Molecular dynamics
(MD) simulations have become an indispensable
tool to investigate phase separation in model membrane systems. In
particular, simulations based on coarse-grained (CG) models have found
widespread use due to their increased computational efficiency, allowing
for simulations of multicomponent lipid bilayers undergoing phase
separation into liquid-ordered and liquid-disordered domains. Here,
we show that a significant temperature difference between molecule
types can artificially arise in CG MD membrane simulations with the
standard Martini simulation parameters in GROMACS. In particular,
the linear constraint solver (LINCS) algorithm does not converge with
its default settings, resulting in serious temperature differences
between molecules in a time step-dependent manner. We demonstrate
that the underlying reason for this behavior is the presence of highly
constrained moieties, such as cholesterol. Their presence can critically
impact numerous structural and dynamic membrane properties obtained
from such simulations. Furthermore, any preference of these molecules
toward a certain membrane phase can lead to spatial temperature gradients,
which can amplify the degree of phase separation or even induce it
in compositions that would otherwise mix well. We systematically investigated
the effect of the integration time step and LINCS settings on membrane
properties. Our data show that for cholesterol-containing membranes,
a time step of 20 fs should be combined with at least lincs_iter = 2 and lincs_order = 12, while using a time
step of 30 fs requires at least lincs_iter =
3 and lincs_order = 12 to bring the temperature
differences to a level where they do not perturb central membrane
properties. Moreover, we show that in cases where stricter LINCS settings
are computationally too demanding, coupling the lipids in multiple
groups to the temperature bath offers a practical workaround to the
problem, although the validity of this approach should be further
verified. Finally, we show that similar temperature gradients can
also emerge in atomistic simulations using the CHARMM force field
in combination with settings that allow for a 5 fs integration step.