Abhishek Acharya

• Antibiotics enter the bacterial cells through the outer membrane diffusion channels called porins. The antibiotic permeation process through porins is of immediate interest and the understanding is expected to aid the development of antibacterial drugs with improved efficacy. The accurate estimation of free energy for translocation is a prerequisite for obtaining quantitative estimates from simulations which would enable a meaningful comparison of different antibiotic permeation mechanisms. This goal, however, has proved to be a significant challenge in the studies on bulky antibiotics, presumably due to a number of slow modes that govern the permeation process. Umbrella sampling and well-tempered metadynamics, that have been extensively used in the field, are limited in the number of degrees of freedom that can be simultaneously biased. In recent years, several methods have been developed that allow biasing simultaneously more degrees of freedom. The primary objective of the present thesis is to examine a few temperature acceleration-based sampling schemes for the enhanced exploration of antibiotic permeation pathways. Subsequently, the temperature accelerated sliced sampling method has been applied to the study of permeation pathways for a few antibiotics. The method, in combination with applied field simulations, is used to uncover the mechanistic aspects of L3 conformational dynamics in antibiotic permeation and voltage gating. The findings provide a strong rationale for the fast permeation of positive and zwitterionic antibiotics reported in experiments. Finally, the combination of a Brownian dynamics scheme with the temperature accelerated molecular dynamics method has been used for the fast and approximate estimation of antibiotic permeability constants.