Antibody-LPS interactions in invasive non-typhoidal Salmonella infections: Coarse-grained simulations of outer membrane dynamics

Invasive non-typhoidal Salmonella (iNTS) infection remains a significant public health concern, particularly in regions with a high incidence rate. Despite the urgency, there is a conspicuous absence of a licensed vaccine against iNTS. Developing an effective vaccine, capable of conferring protection against multiple Salmonella serotypes, stands as a paramount goal in combating this deadly pathogen. A critical but underexplored aspect of vaccine design is the correlation between antibody behavior and the diverse structural configurations of O-antigens (O-Ag) within the bacterial outer membrane. In this study, we modeled the outer membrane of two prevalent iNTS serotypes, Salmonella enterica Enteritidis (SEn) and Salmonella enterica Typhimurium (STm), as well as the outer membrane proteins OmpD and OmpA. We utilized coarse-grained molecular dynamics (CGMD) simulations to simulate larger systems than are accessible with atomistic MD, offering a comprehensive view of their dynamic interactions over extended timescales. By varying the lengths of O4 and O9 O-Ag repeats, from as short as none to as many as 35 O-Ag repeats, we generated a total of 32 distinct systems, each simulated for multiple microseconds. Analysis of these CG simulations sheds light on the intricate interplay between Salmonella's outer envelope structure, mobility, and antibody accessibility, providing valuable insights that will benefit the development of effective iNTS vaccines.