Vaccine development for group A streptococcus
MD can be used to sample the conformations a peptide assumes in its natural movement. Sampling these conformations allows for the identification of structurally-related peptides.
PEP-FOLD model of the N-terminus of M12, a GAS serotype commonly linked to pharyngeal disease in established market economy countries.
Can MD be used to identify similar side-chain conformations between immunologically-related peptides?
Group A streptococcus (GAS) is an ubiquitous human pathogen that causes an estimated 600 million infections worldwide each year. The acute infections range from uncomplicated pharyngitis, cellulitis, and pyoderma to life-threatening infections that include necrotizing fasciitis, bacteremia, pneumonia, and streptococcal toxic shock syndrome. Mild, even asymptomatic infections can be followed by serious autoimmune diseases, the most significant being acute rheumatic fever (ARF) and rheumatic heart disease (RHD). One recent study has suggested that the prevalence of RHD in children in developing countries may actually be 10 times higher than previously predicted, One potential GAS vaccine target is a coiled coil membrane protein known as the M protein. The N-terminus of the M protein has shown in previous studies to elicit antibodies that are capable of binding to multiple M protein isoforms in a phenomenon known as cross-reactivity. The goal of this research is to model the N-termini of clinically-relevant M protein isoforms and formulate new methodologies to predict cross-reactivity in silico.
MD can be used to detect global structural changes. The two images are structures of the same peptide at different frames of an MD simulation. The goal is to simulate immunologically-related or cross-reactive GAS peptides and identify structural similarities. If structural similarities are found, this would suggest there is a structural basis to cross-reactivity. Therefore, peptides of unknown immunological relationship could be simulated to identify structural similarities and thereby predict cross-reactivity.
MD detects local structural changes including the formation and breakage of hydrogen bonds as seen here by the blue dotted line between lysine (blue) and glutamate (cyan). The characterization of both global and local changes between immunologically-related peptides may reveal the structural basis for cross-reactivity among GAS serotypes.
This project is done in collaboration with Dr. James Dale at the University of Tennessee Memphis Health Science Center and Dr. Jeremy Smith at the University of Tennessee, Knoxville and Oak Ridge National Laboratory (ORNL).