KTH Royal Institute of Technology
The cellular membrane acts as a barrier to isolate the cell’s inside from the outside world. To communicate with its environment, the cell uses membrane proteins that facilitate the transport and permeation of otherwise impermeant species. Dysfunction of these proteins lead to diseases such as epilepsy, heart arrhythmias or paralysis. These proteins are also privileged drug targets since they are accessible from the outside of the cell.
Recent developments in structural biology have provided us with static structures of these exquisite molecular machines, yielding the first insights into how these proteins may perform their function. We provide further insight into their function and regulation by their environment by using molecular dynamics simulations, which we run on high performance computers afforded by the Swedish National Infrastructure for Computing. This allows not only to understand the complex interplay between the ion channel and its environment, particularly components of the cell membrane but also to delve into the details of how these molecular machines harness energy and perform their role at the atomistic level.
We collaborate with groups all over the world to tackle questions of biomedical relevance in a collaborative fashion. For example, we investigate the fundamental aspects of heart channel activation with electrophysiologists from the University of Wisconsin, Madison; we understand and design novel drugs to treat epilepsy with researchers from the University of Linköping or else, we gain access to the molecular level details of G-Protein coupled receptor activation with computational chemists from the University of Uppsala
MA Kasimova, E Lindahl, L Delemotte “Determining the molecular basis of voltage sensitivity in membrane proteins” The Journal of general physiology, 2018, 150 (10), 1444-1458
AM Westerlund, L Delemotte “Effect of Ca2+ on the promiscuous target-protein binding of calmodulin” PLoS computational biology, 2018, 14 (4), e1006072
AI Fernández-Mariño, TJ Harpole, K Oelstrom, L Delemotte, B Chanda “Gating interaction maps reveal a noncanonical electromechanical coupling mode in the Shaker K+ channel” Nature structural & molecular biology, 2018, 25 (4), 320
TJ Harpole, L Delemotte “Conformational landscapes of membrane proteins delineated by enhanced sampling molecular dynamics simulations” Biochimica et Biophysica Acta (BBA)-Biomembranes, 2018, 1860 (4), 909-926
AM Westerlund, TJ Harpole, C Blau, L Delemotte “Inference of Calmodulin’s Ca2+-Dependent Free Energy Landscapes via Gaussian Mixture Model Validation” Journal of chemical theory and computation, 2017, 14 (1), 63-71
L Delemotte, MA Kasimova, ML Klein, M Tarek, V Carnevale “Free-energy landscape of ion-channel voltage-sensor-domain activation”
Proceedings of the National Academy of Sciences USA, 2015, 112 (1), 124-129
L Delemotte, M Tarek, ML Klein, C Amaral, W Treptow “Intermediate states of the Kv1. 2 voltage sensor from atomistic molecular dynamics simulations”, Proceedings of the National Academy of Sciences 108 (15), 6109-6114