Role of receptor clustering for the efficient oligomer formation of pore forming toxins

A number of bacteria toxins are capable of lysing cellular membranes. Responsible for this process are bacterial factors (peptides or proteins) which are excreted by the bacterium and spontaneously bind to cellular membranes as monomers and oligomerise on the membrane. Finally, the oligomer undergoes a structural rearrangement leading to a transmembrane-pore, causing efflux of intracellular substances. The whole process can be divided into three steps: binding, oligomerisation and insertion. The first step, binding to the membranes, occurs to specific receptors which are naturally present on the target membrane. The density of this anchor-molecule on the membrane, its affinity for the toxin as well as the probability of an encounter of two membrane-bound toxins determine the speed of oligomerisation. Once the oligomer has reached a certain size, which is toxin-dependent, the final transition to the pore takes place with a certain probability. The aim of this project is to investigate for which values of the crucial parameters an efficient pore formation is possible. To this end the kinetics of the process will be simulated as Markov chain in order to obtain information about qualitative and quantitative properties. In this model system the membrane with its binding sites (= receptors) is represented by a two-dimensional grid. Adding and removing particles simulates the binding of the monomer, and a coalescing random-walk on the grid-vertices models the oligomerisation process. The diffusion-constants, coalescence rates etc. will be varied in a broad range in order to find out for which range of values the experimental observations can be reproduced. Finally, we hope to obtain an estimate on the maximal amplification which can be obtained just by clustering binding sites compared to random distribution.