Event Title
Co-operativity in Hydrogen-Bonding Networks Dictates Conformational Sampling of a Pneumococcal Fibronectin-binding Adhesive Protein
Faculty Sponsor
Dhruva Chakravorty
Submission Type
Poster
Description
We study the effect of networks of non-covalent interactions on the conformational dynamics of the Streptococcus pneumoniae virulence factor, PfbA. Multi-microsecond molecular dynamics simulations of the apo, Ca2+-bound and Mn2+/Ca2+-bound surface –binding protein in water and sugar solutions help identify potential glycan recognition sites and develop a hypothesis for the mechanism of surface binding. We find that while residues in the β-domain of PfbA remain rigid over the course of microseconds, residues in the α/β domain undergo a bending movement akin to a swinging pendulum. Surprising, metal ion binding has a limited effect on the conformational dynamics of the protein. We identify networks of non-covalent interactions including hydrogen bonds and π-π stacks motifs that are maintained over the course of our simulations. We further model the entire protein to develop a hypothesis of how the α domain is involved in signaling and protein recognition. Our quantum mechanical calculations determine that a strong cooperative effect is present in hydrogen bonding pathways containing asparagine residues that accounts for an almost 20% increase in hydrogen bond strength. Our calculations further suggest that moderate amounts of charge transfer across these networks may likely contribute to this phenomenon. A Ramachandran analysis finds that residues in the region connecting the two domains alternated between β-sheets and α-helix like conformations. Our analyses find the α-helical regions around Gly184 and Gln185 to undergo conformational changes that may play a role in plasminogen binding. Our simulations further find support for a putative carbohydrate-binding site. Conformations of PfbA docked against plasminogen expand our understanding of the interaction at this interface. Overall, our study provides insights that will help develop a pharmaceutical means to inhibit S. pneumonia virulence.
Co-operativity in Hydrogen-Bonding Networks Dictates Conformational Sampling of a Pneumococcal Fibronectin-binding Adhesive Protein
We study the effect of networks of non-covalent interactions on the conformational dynamics of the Streptococcus pneumoniae virulence factor, PfbA. Multi-microsecond molecular dynamics simulations of the apo, Ca2+-bound and Mn2+/Ca2+-bound surface –binding protein in water and sugar solutions help identify potential glycan recognition sites and develop a hypothesis for the mechanism of surface binding. We find that while residues in the β-domain of PfbA remain rigid over the course of microseconds, residues in the α/β domain undergo a bending movement akin to a swinging pendulum. Surprising, metal ion binding has a limited effect on the conformational dynamics of the protein. We identify networks of non-covalent interactions including hydrogen bonds and π-π stacks motifs that are maintained over the course of our simulations. We further model the entire protein to develop a hypothesis of how the α domain is involved in signaling and protein recognition. Our quantum mechanical calculations determine that a strong cooperative effect is present in hydrogen bonding pathways containing asparagine residues that accounts for an almost 20% increase in hydrogen bond strength. Our calculations further suggest that moderate amounts of charge transfer across these networks may likely contribute to this phenomenon. A Ramachandran analysis finds that residues in the region connecting the two domains alternated between β-sheets and α-helix like conformations. Our analyses find the α-helical regions around Gly184 and Gln185 to undergo conformational changes that may play a role in plasminogen binding. Our simulations further find support for a putative carbohydrate-binding site. Conformations of PfbA docked against plasminogen expand our understanding of the interaction at this interface. Overall, our study provides insights that will help develop a pharmaceutical means to inhibit S. pneumonia virulence.
Comments
5th place, Poster