INVESTIGATION INTO THE AGGREGATIONS OF ISOMERIC ANTIBACTERIAL OLIGOTHIOETHERAMIDES USING MULTI-SCALE MOLECULAR DYNAMICS SIMULATIONS

Cationic charge and hydrophobicity have been commonly identified as factors which drive the potency of antibacterial peptides (AMPs) and their mimics. However, these two factors have been determined to be inexhaustive, with the added difficulty of differentiating between affecting bacterial and mammalian cells. Hence, there is an incentive to determine new parameters to identify antibacterial propensities in terms of membrane disruption to overcome such limitations. Recent research in Prof. Christopher Alabi’s lab at Cornell University identified a pair of stereo-isomeric antibacterial oligothioetheramides (oligoTEAs), which have the same cationic charge and hydrophobicity, but an approximately 10-fold difference in antibacterial potency. This difference could be employed to discover a new metric relevant to designing and optimizing new antibacterials. Results from previous experimental and computational studies on this specific pair of oligoTEAs are inconclusive to determine the difference between the detailed mechanisms of two isomers, let alone find new differential metrics. In this work, Molecular Dynamics simulations were performed with both All-Atom and Coarse-Grained models in order to investigate thermodynamic and physical properties that might help in this to understand the differences between the two isomers in the processes associated with oligoTEAs aggregation. The studies in All-Atom Molecular Dynamics simulations indicated that para- and meta- oligoTEAs had very similar aggregation processes without the presence of bacterial membrane. The studies in Coarse-Grained Molecular Dynamics simulations did not show the desired aggregations with oligoTEAs and lipid molecules, but the binding of para-oligoTEAs to the membrane surface did induce a larger membrane disruption. Since these current findings cannot explicitly explain the potency differences between two isomeric oligoTEAs, further computational studies are still required to be carried on