Anales RANF

S11-01 CONFORMATIONAL CHANGE IN P2XR – INSIGHTS FROM MOLECULAR DYNAMICS SIMULATIONS R. Schmid University of Leicester, Leicester, United Kingdom With X-ray structures of different P2X receptor homologs (and homology models derived from them) in closed, open and desensitized states available (for review, see Pasqualetto et al., Front. Pharmacol., 9 , 58, (2018)) we can start to decipher the transitions between such states at an atomistic level. In my lab we use molecular dynamics simulations to monitor the response of receptors to “disturbances” such as mutations or (un)binding events over time, and to study the dynamics of structural variation. Recent progress in molecular dynamics algorithms and the advent of GPU hardware allows us to routinely extend atomistic simulations of P2XRs into the low micro second range. While this time resolution is by no means close to the millisecond to second time scales on which transitions between states typically occur, it enables us to investigate initial responses of a receptor to, for instance, binding or unbinding events. In my talk I will focus on two aspects our recent work on P2XRs. In the first part I will present data on binding and unbinding of agonists and antagonists to P2XRs, and how this affects receptor structure and dynamics. The second part covers effects of mutations on the stability and dynamics of the intracellular cap, and I will discuss consequences on transitioning between different receptor states.