Molecular dynamics studies of peptide-membrane interactions: insights from coarse-grained models
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.