Karunakar Reddy Pothula

• Bacterial outer membrane (OM) channels are of major pharmaceutical interest in the field of infectious diseases, since they act as gateways for the influx of antibiotics. The research work reported in this thesis is aimed at understanding the common principles in the functionality of these channels from a molecular perspective. In the first part, we dealt with the nutrient acquisition mechanisms by a OM transporter complex. SusCD, a transporter from Bacteroides thetaiotaomicron, was investigated using MD simulations. Bacteroides species are highly populated in the human large intestine and plays a significant role in digestion and obesity. The survival of these organisms depend on their ability to acquire undigested nutrients from the highly competitive gut environment by OM transporter complexes. In this thesis, we presented a generalized mechanism for the nutrient acquisition by SusCD-like OM complexes. MD simulations revealed a "pedal-bin mechanism" for the particular SusCD transport machine which could be applicable to other transporters. Given the unknown specific functions of many OM proteins, this study improves the molecular understanding of transport mechanisms by OM transporters. The second part of the thesis aimed at understanding functional properties, i.e., gating and selective nutrient uptake, of passive diffusion channels. These channels are dynamic and exists in multiple pore sizes to control the influx of nutrients across the OM. MD simulations identified the crucial residue driving the opening and closing of the OpdH channel. Furthermore, we investigated the functional role and selective uptake mechanism of OpdH channel using MD simulations. Free-energy calculations revealed thermodynamic insights into the selective uptake mechanism of the OpdH channel and its preference for the uptake of succinate from the environment. Our results show that OpdH selectivity can be explained on the basis of "size-exclusion" principle.