(773g) Predicting the Dimer Structure of Defensins Using a Combined Simulation Strategy

Defensins are cationic cysteine-rich small molecules with molecular masses ranging from 2 to 6 kDa. They can be classified into alpha, beta and theta categories. They are important to the human innate immune system, and have a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative bacteria. Defensins have been shown to form oligomers, and human defensins have been shown to function in a dimer or even higher ordered oligomer form.

Human beta defensin 3 (hBD-3) is believed to function as a dimer, as Schibli et al [i]in 2002 predicted a symmetric dimer structure of hBD-3 using NMR. On the other hand, the noncovalent electrostatic interaction contributes to the diverse binding interfaces of hBD-3 dimer as predicted from docking software. In order to solve the discrepancy and predict a trustable dimer structure of hBD-3, a combined simulation strategy was developed in this project, which uses replica-exchange implicit solvent CHARMM simulation to predict the initial dimer structure, then uses explicit solvent all atom molecular dynamics simulations to refine the structure. The method was initially tested on both human alpha defensin 5 (HD-5) and human beta defensin 2 (hBD-2), and was proven to work well. The same strategy was applied on hBD-3 to predict its trustable dimer structure, which agrees with experimental findings.