Continuum Approaches to Understanding Ion and Peptide
Interactions with the Membrane
Naomi R. Latorraca
Keith M. Callenberg
Jon P. Boyle
Received: 12 October 2013 / Accepted: 22 February 2014 / Published online: 21 March 2014
Ó Springer Science+Business Media New York 2014
Abstract Experimental and computational studies have
shown that cellular membranes deform to stabilize the
inclusion of transmembrane (TM) proteins harboring
charge. Recent analysis suggests that membrane bending
helps to expose charged and polar residues to the aqueous
environment and polar head groups. We previously used
elasticity theory to identify membrane distortions that
minimize the insertion of charged TM peptides into the
membrane. Here, we extend our work by showing that it
also provides a novel, computationally efﬁcient method for
exploring the energetics of ion and small peptide penetra-
tion into membranes. First, we show that the continuum
method accurately reproduces energy proﬁles and mem-
brane shapes generated from molecular simulations of bare
ion permeation at a fraction of the computational cost.
Next, we demonstrate that the dependence of the ion
insertion energy on the membrane thickness arises pri-
marily from the elastic properties of the membrane.
Moreover, the continuum model readily provides a free
energy decomposition into components not easily deter-
mined from molecular dynamics. Finally, we show that the
energetics of membrane deformation strongly depend on
membrane patch size both for ions and peptides. This
dependence is particularly strong for peptides based on
simulations of a known amphipathic, membrane binding
peptide from the human pathogen Toxoplasma gondii.In
total, we address shortcomings and advantages that arise
from using a variety of computational methods in distinct
Keywords Ion permeation Á Membrane elasticity Á
Continuum Á Coarse grained Á Rhoptry protein 5 (ROP5)
The cell membrane serves as a critical barrier differenti-
ating the interior of the cell from the extracellular medium.
It is inextricably linked to cellular identity—without a
membrane, a cell cannot control its internal chemistry.
Loss of membrane integrity often leads to cell death, and
organisms have evolved strategies to kill other cells by
attacking their membranes, as in the mechanisms of many
antibiotics. Strikingly, cells induce their own deaths by
compromising the integrity of their membranes during
apoptosis through decoupling the cytoskeletal network
from the membrane, which leads to blebbing (Mills et al.
Chemical and physical principles underlie the mem-
brane’s dual role as a barrier to the external environment
and regulator of nutrient transport into and out of the cell.
Naomi R. Latorraca and Keith M. Callenberg have contributed
equally to this work.
N. R. Latorraca Á J. P. Boyle Á M. Grabe (&)
Department of Biological Sciences, University of Pittsburgh,
4249 Fifth Avenue, Pittsburgh, PA 15260, USA
K. M. Callenberg
Carnegie Mellon University-University of Pittsburgh Ph.D.
Program in Computational Biology, 4249 Fifth Avenue,
Pittsburgh, PA 15260, USA
Department of Computational & Systems Biology, University of
Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA
Department of Pharmaceutical Chemistry, Cardiovascular
Research Institute, University of California, San Francisco, 555
Mission Bay Blvd South, San Francisco, CA 94158, USA
J Membrane Biol (2014) 247:395–408