KTH Royal Institute of Technology
The cellular membrane acts as a barrier to isolate the cell’s inside from the outside world. In our research group, we use large-scale computer simulations to study the molecular mechanisms of various phenomena happening at the plasma membrane.
To communicate with its environment, the cell uses membrane proteins that facilitate the transport and permeation of otherwise impermeant species. Excitable cells such as neurons, heart or muscle cells, specifically, function by initiating and propagating electrical signals, in the form of controlled transport of selected ions across the cellular membrane. The proteins involved in this transport are called ion channels and their dysfunction leads to a variety of inherited diseases (heart arrhythmias, epilepsies, periodic paralyses). To understand the minute details of the working cycles of these molecular machines, we employ multi-scale molecular dynamics simulations. This enables to understand the complex interplay between the ion channel and its environment, particularly the lipid molecules of the cell membrane and the components of the intra- and extracellular solution.
We resort to state-of the art enhanced sampling methods and use kinetic models to compute properties that can be directly compared with experimental (electrophysiology) measurements. This serves to validate the computational models used, such that we can trust their predictive power.
To understand the commonalities and differences between the structure and function of different related membrane proteins, we use protein sequence analysis tools. In this way, we can reconstitute the evolutionary design principles of specific protein motifs and understand shared functional mechanisms across membrane protein families. This information can be further exploited to design protein mutants with desired properties.
Finally, we collaborate with experimental groups to tackle questions of biomedical relevance, such as understanding the effect of genetic mutations. For example, specific mutations may cause the appearance of aberrant leak currents, which can cause heart arrhythmias. Understanding the details of the malfunction can serve as a basis to design more efficient drugs.
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
A Moreau, P Gosselin-Badaroudine, L Delemotte, ML Klein, M Chahine “Gating pore currents are defects in common with two Nav1. 5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy” J. Gen. Physiol. 2015, 145 (2), 93-106
E Palovcak, L Delemotte, ML Klein, V Carnevale “Comparative sequence analysis suggests a conserved gating mechanism for TRP channels” J. Gen. Physiol., 2015, 146 (1), 37-50
MA Kasimova, M Tarek, AK Shaytan, KV Shaitan and L Delemotte, “Voltage-gated ion channel modulation by lipids: Insights from molecular dynamics simulations” BBA-Biomembranes, 2014, 1838 (5), 1322-1331 (A)
M Breton, L Delemotte, A Silve, L Mir and M Tarek, “Transport of siRNA through Lipid Membranes driven by Nanosecond Electric Pulses: an Experimental and Computational Study” J. Am. Chem. Soc., 2012, 134 (34), 13938-41