In this exciting project the PhD student will make use of advanced computational methodologies to assess the molecular basis of the pathophysiology of TRPC channels. Starting from the simulation of the dynamics of these channels, the PhD student will establish new descriptors to navigate the functional mutational landscape in TRPC channels. The PhD student will benefit of the experimental know-how within TRPC.at to validate their methodology. The generated information will be used to look for new probes and potential drugs to monitor and modulate the response of these extraordinary channels.
Project Details
Background:
Calcium ion channels mediate neurotransmission and cardiac function by fixing and modulating the calcium concentrations in the cytoplasm and cellular organelles and constitute one of the central pillars of cell signaling. Thus, the dysregulation of these calcium ion channels and related effectors is associated with different pathophysiological conditions in cardiopathies, pain, cancer, neurological disorders, and respiratory disorders, amongst others. The members of the classical transient receptor potential (TRPC) subgroup of the TRP superfamily are nonselective cation channels located at the human cell plasma membrane. In the last years, the structures of different TRP channels have been solved, which has stimulated their potential as therapeutic targets.1 However, a general understanding of how amino acid mutations on TRPC impact functionality, dynamics, and pathophysiology, or their binding to effectors, lipids, probes or potential drugs to these channels, remains elusive.
Hypothesis and Objectives:
In this project we will investigate the pathophysiology of TRPC3, and other related TRPC channels in the context of lipid membranes by means of advanced simulation techniques. Starting from the all-atom representation of the studied macromolecules, we will generate conformational ensembles to study the role of the network of residues on the dynamics of the channel as well as the degree of coupling of this nextwork between them. This information will be used to shed rationale on the role of each of the positions of these channels on specific diseases and to predict their impact in other physiological conditions. Moreover, we will design and search for binders and probes of different natures able to modulate TRPC function.
Methodology:
The PhD student will be trained in advanced molecular dynamics simulation techniques as well as in a variety of modeling approaches for biological systems. The PhD candidate will learn different de novo algorithms for the prediction of the structure of TRPC channels and will simulate the dynamics of them using from classical force-field molecular dynamics simulations, metadynamics, accelerated Gaussian molecular dynamics, to coarse-grained approaches, amongst others. All these data will be used as a training dataset for the elucidation of a set of descriptors per residue useful to predict their role in the context of the pathophysiology of the channel:2 dynamics, connectivity with different regions of the channel, or stability, amongst others. Additionally, we will search for new peptide binders and probes able to modulate TRPC function.3 In all cases, the student will benefit from the close and direct collaboration with the experimental team, enabling an iterative validation and refinement of the computational data.
References
- Koivisto, AP., Belvisi, M.G., Gaudet, R. et al. Advances in TRP channel drug discovery: from target validation to clinical studies. Nat Rev Drug Discov 21, 41–59 (2022).
- Mandl Š, Di Geronimo B, Alonso-Gil S, Grininger C, George G, Ferstl U, et al. A new view of missense mutations in α-mannosidosis using molecular dynamics conformational ensembles. Protein Science. 34, e70080 (2025)
- Lichtenegger, M., Tiapko, O., Svobodova, B. et al. An optically controlled probe identifies lipid-gating fenestrations within the TRPC3 channel. Nat Chem Biol 14, 396–404 (2018)
People Involved
Primary supervisor: Pedro Sánchez-Murcia