| dc.description.abstract | The nonstructural protein 1 (NS1) of the 1918 Spanish influenza A virus hijacks N-terminal
Src-homology 3 (nSH3) domain of host’s cellular CrkII with exceptionally high affinity through its
proline-rich motif (PRM NS1). By comparison, cellular PRMs are intrinsically disordered proteins
mediating protein-protein interactions only with weak binding affinities. Therefore, it’s critical to
elucidate the thermodynamic difference between the binding of viral PRM and cellular PRMs. For
that reason, molecular dynamics (MD) simulation is used to provide insights at an atomistic level.
This dissertation aims to further the understanding of nSH3:PRM binding via: (i) studying the
role of fuzzy interactions of bound PRM NS1, (ii) dissecting and comparing the entropic contribution
for the binding of nSH3 by PRM NS1 (viral) and PRM cAbl (cellular, from Abl kinase), and (iii)
developing a method for evaluating solvation contribution upon complexation.
For aim (i), MD simulations of nSH3:PRM NS1 are compared with crystal structures and fuzzy
interactions are shown to enhance the long-range electrostatic interactions by reducing their average pairwise distances.
For aim (ii), the associated conformational entropy are calculated with binding of two PRMs to
the nSH3 domain. Different side chain/backbone contributions are observed, with implications for
structure-based entropic contribution. At residue level, entropy “hotspots” are identified, some of
which locate distal to the binding interface, indicating an allosteric role of ligand for downstream
regulation. As a result of forming more extensive contacts, nSH3:PRM NS1 shows greater entropy
loss than nSH3:PRM cAbl.
For aim (iii), a density-based solvation analysis is developed. The result reveals a coupling effect between protein dynamics and local solvation contribution, via which the viral ligand manages
to decrease the solvation penalty to enhance its binding affinity.
In sum, this dissertation reveals PRM NS1 ’s distinctive molecular recognition mechanisms underlying fuzzy interaction, conformational entropy, and surface hydration. And our newly developed solvation analysis is expected to be applied to the hydration effect of other biomolecules. | en |
