THESIS
2016
5, that is, 7 pages, 77 pages : illustrations (some color) ; 30 cm
Abstract
MAGUKs (membrane-associated guanylate kinases) are a family of scaffold proteins. They
are distributed in both pre- and post-synaptic sides of excitatory synapses and function in
diverse cellular processes. Dysfunction of MAGUKs and mutations of MAGUKs-binding
proteins have been shown to play important roles in mental disorders, such as ASD (autism
spectrum disorder) and Williams syndrome. GK (guanylate kinases like) domain is one of the
conserved domains and acts as binding module to mediate the binding between MAGUKs and
other synaptic proteins. As the regulation of the MAGUKs-associated synaptic protein
complex is related to ASD and other mental illnesses, it is useful to design inhibitors against
the GK domain that are effective and highly specific in cellular environment. I...[
Read more ]
MAGUKs (membrane-associated guanylate kinases) are a family of scaffold proteins. They
are distributed in both pre- and post-synaptic sides of excitatory synapses and function in
diverse cellular processes. Dysfunction of MAGUKs and mutations of MAGUKs-binding
proteins have been shown to play important roles in mental disorders, such as ASD (autism
spectrum disorder) and Williams syndrome. GK (guanylate kinases like) domain is one of the
conserved domains and acts as binding module to mediate the binding between MAGUKs and
other synaptic proteins. As the regulation of the MAGUKs-associated synaptic protein
complex is related to ASD and other mental illnesses, it is useful to design inhibitors against
the GK domain that are effective and highly specific in cellular environment. In this thesis,
we used computational biology and chemical biology approaches to design such inhibitor
peptides. We have obtained dephosphorylated peptides that bind to the GK domain with
comparable affinities of natural phosphorylated ligands. These dephosphorylated peptides are
expected to be more stable and effective inhibitors in cellular environment than their natural
phosphorylated counterpart. These peptides are first identified through a computational
iterative sequence optimization protocol combining molecular dynamics simulations and
MMPBSA (molecular mechanics energy combined with the Poisson-Boltzmann and surface
area continuum solvation) binding free energy calculation method and then validated by
biochemical experiments. Additional trials suggest that adding staples to the found peptides
may further enhance their structural stability compared to non-stapled ones. We also showed
that compounds with low molecular weights are not effect inhibitors of the GK domain
because of their weak solubility.
Post a Comment