Molecular dynamics studies of peptide-membrane interactions: insights from coarse-grained models
Abstract
Peptide-membrane interactions play an important role in a number of biological processes,
such as antimicrobial defence mechanisms, viral translocation, membrane fusion
and functions ofmembrane proteins. In particular, amphipathic α-helical peptides
comprise a large family of membrane-active peptides that could exhibit a broad range
of biological activities. A membrane, interacting with an amphipathic α-helical peptide,
may experience a number of possible structural transitions, including stretching,
reorganization of lipid molecules, formation of defects, transient and stable pores, formation
of vesicles, endo- and pinocytosis and other phenomena. Naturally, theoretical
and experimental studies of these interactions have been an intense on-going area of
research. However, complete understanding of the relationship between the structure
of the peptide and themechanismof interaction it induces, as well asmolecular details
of this process, still remain elusive. Lack of this knowledge is a key challenge in our
efforts to elucidate some of the biological functions of membrane active peptides or to
design peptides with tailored functionalities that can be exploited in drug delivery or
antimicrobial strategies. In principle,molecular dynamics is a powerful research tool to study peptide-membrane
interactions, which can provide a detailed description of these processes on molecular
level. However, a model operating on the appropriate time and length scale is imperative
in this description. In this study, we adopt a coarse-grained approach where the
accessible simulation time and length scales reach microseconds and tens of nanometers,
respectively. Thus, the two key objectives of this study are to validate the applicability
of the adopted coarse-grained approach to the study of peptide-membrane
interactions and to provide a systematic description of these interactions as a function
of peptide structure and surface chemistry.
We applied the adopted strategy to a range of peptide systems, whose behaviour has
been well established in either experiments or detailed atomistic simulations and outlined
the scope and applicability of the coarse-grained model. We generated some
useful insights on the relationship between the structure of the peptides and themechanism
of peptide-membrane interactions. Particularly interesting results have been
obtained for LS3, a membrane spanning peptide, with a propensity to self-assembly
into ion-conducting channels. Firstly, we captured, for the first time, the complete
process of self-assembly of LS3 into a hexameric ion-conducting channel and explored
its properties. The channel has structure of a barrel-stave pore with peptides aligned
along the lipid tails. However, we discovered that a shorter version of the peptide
leads to a more disordered, less stable structure often classified as a toroidal pore.
This link between two types of pores has been established for the first time and opens
interesting opportunities in tuning peptide structures for a particular pore-inducing
mechanism. We also established that different classes of peptides can be uniquely
characterized by the distinct energy profile as they cross the membrane. Finally, we
extended this investigation to the internalization mechanisms of more complex entities
such as peptide complexes and nanoparticles. Coarse-grained steered molecular
dynamics simulations of these model systems are performed and some preliminary
results are presented in this thesis.
To summarize, in this thesis, we demonstrate that coarse-grained models can be successfully
used to underpin peptide interaction and self-assembly processes in the presence
of membranes in their full complexity. We believe that these simulations can
be used to guide the design of peptides with tailored functionalities for applications such as drug delivery vectors and antimicrobial systems. This study also suggests that
coarse-grained simulations can be used as an efficient way to generate initial configurations
for more detailed atomistic simulations. These multiscale simulation ideas will
be a natural future extension of this work.