Insights into the Energetics of Membrane-Bound Peptides : Towards an Understanding of the Structural Organisation of Membrane Proteins

A large number of key cellular functions such as signalling and transport are performed and regulated by membrane proteins. The focus of this thesis is on a sub-class of membrane proteins, namely the monotopic and bitopic peptides. Analysis of several aspects of these peptides such as their orientation, electrostatics and association is reported here. The environment of these peptides is represented by a continuum model that distinguishes between water, membrane core and head-group region. The orientation of membrane peptides such as glycophorin A and melittin is calculated and reproduces the experimentally-calculated tilt angles. The length dependence of synthetic peptides such as WALPs is reproduced and found to depend on the cost of cavity formation in the aqueous layer. It is shown that the solvent reaction field plays a crucial role in determining the orientation of polypeptides. The reaction field is also shown to screen the helix dipole of membrane-bound helices depending on the proximity and geometry of the aqueous phase relative to the helix termini. As a result, the helix dipole of transmembrane helices is found to decrease with peptide length. The analysis is extended to helices in soluble proteins and rules of thumb are established to estimate the effective helix dipole from visual inspection of protein structures. The association of glycophorin A helices is modelled and the decomposition of free energy of dimerisation shows a favourable contribution from the residues experimentally implicated to contribute to the process. The association of erythropoietin receptor transmembrane dimers and that of its mutants is also modelled. The inefficient lipid raft localisation of the T242N mutant is proposed to be related to its helix packing. The thesis provides insight into the structural organisation and energetics of membrane proteins