Thesis (Ph.D.)--University of Rochester School of Medicine & Dentistry. Dept. of Biochemistry and Biophysics, 2016.
The increasing number of antibiotic-resistant strains has been a severe medical
problem in the 21st century. This necessitates the development of new antibiotics
that operate via mechanisms that are less likely to incur evolved resistance. One
class of promising candidates is antimicrobial lipopeptides (AMLPs) which are
short peptides conjugated to a hydrophobic acyl chain. Experiments have demonstrated
these AMLPs’ activities both in vivo and in vitro, which correlate with their
abilities to permeabilize model membranes. This leads to the fundamental hypothesis
that these AMLPs act by preferentially perturbing microbial membranes.
To understand their mechanisms of membrane interaction, we ran long time-scale
molecular dynamics simulations to quantitatively examine their interactions with
model membrane bilayers. We used a coarse-grained method and enhanced sampling
algorithms to uncover the thermodynamics governing these AMLPs’ binding
to membranes. In Chapter 2, we calculate AMLP’s membrane binding free energy
and show that the hydrophobic acyl chain is mainly responsible for AMLPs’ membrane
affinity, while the peptide portion determines the membrane selectivity. In
Chapter 3, we introduce a novel reaction coordinate based on hydrophobic contacts
and apply it to explore the thermodynamics of oligomerization of these AMLPs.It was found that their oligomerization is polydisperse. Moreover, we discovered
that the AMLP oligomers bind to membranes via mechanisms distinct from the
monomeric cases; while the binding is thermodynamically favorable, it has to overcome
significant free energy barriers and the height of these barriers depends on the
membrane composition. This suggests that these AMLPs’ selectivity towards the
microbial membranes is driven by both thermodynamics and kinetics. This novel
mechanism highlights the importance of AMLPs’ oligomerization in solution to
their antimicrobial activity. To further our understanding of lipopeptide-membrane
interaction, a coarse-grained model of lipids is introduced in Chapter 4 with the goal
of achieving better representation of electrostatics and molecular shape than common
coarse-grained models while retaining most of their computational efficiency.
Along the same line, an efficient algorithm is developed to calculate electric multipole
interactions, which can be applied to the new coarse-grained model. This
algorithm is introduced in Chapter 5.
