| Summary: | <p>Peripheral membrane proteins (PMPs) interact with the cell membrane. They are
important for many cell processes and are important therapeutic targets. This thesis
seeks to investigate the membrane recognition and binding processes that are integral
to the function of two PMP systems. Phosphatidylinositol phosphates (PIPs) are
lipid signaling molecules that play key roles in many cellular processes. The PIP5K1A
kinase catalyses phosphorylation of PI4P to form PIP<sub>2</sub>, which in turn interacts with
membrane and membrane-associated proteins. We present a multiscale simulation
study of the PIP5K1A kinase and its interaction with PIPs in the membrane. The
study showed that the PIP5K1A kinase interacts with PIPs via its activation loop,
leading to reorientation and binding. It also showed that the dimeric PIP5K1A binds
with PIPs via only one catalytic site at a time, which has important implications for
the role of membrane curvature and composition in PMP binding. This is addressed
by large-scale simulations of PIP5K1A signalling. Furthermore, Markov state models
(MSMs) were applied to the activation loop. This work showed that the loop remains
disordered in the membrane but adopts specific conformations that may help explain
its specificity. These methods were extended to another PMP system of interest, α-
synuclein. The results showed that interaction with the membrane is led by the interhelical
region, and offers a structural perspective of a break in the helical structure,
which is supported by experimental studies. This may inform our understanding of α-
synuclein aggregation, and more generally aid in our understanding of PMP signalling.</p>
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