EnLaCES · Energy Landscapes from Cryo-EM and Simulations
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-10-01 → 2023-09-30
- EU contribution
- €160,932
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Energy Landscapes from Cryo-EM and Simulations
The problem being addressed is to better understand structure and dynamics of biological macromolecules using single particle cryo-electron microscopy (CryoEM), which is capable of imaging a large number of particles frozen in a range of structures associated with functional state(s) trapped by sample preparation conditions. It has the potential of revealing complete structural landscapes and how they change under various conditions, providing unprecedented insights into biological mechanisms at the molecular level and enabling greater control for drug discovery. The project has two parts, each facilitating further work with direct importance for society. Our collaborative attitude also benefits society as has been especially evident during the pandemic. One key example was our study on the "Spanish variant” of SARS-CoV-2, which involves several groups across Madrid, Barcelona and Valencia, providing reassurance on the small but significant structural and functional consequences of a potentially worrying mutation that spread across Spain and beyond during summer 2020 and other times during the pandemic. The first objective is the development of new computational methods and pipelines to address this problem using a range of interdisciplinary approaches from fields including statistics, CryoEM image processing and computational biophysics (molecular simulations and related methods). A key aim for this part is the creation of user-friendly, open source software, which will allow other scientists to easily obtain more meaningful results to guide their biological studies and drug/vaccine development projects and will assist other researchers in developing better methods in the future. The second objective is direct application of our new tools as well as existing ones to known biological systems, including AMPA-type glutamate receptors (AMPARs) that are critical in learning and memory and implicated in various diseases, as well as others. In particular, human epidermal growth factor receptors (HERs) that are important causative agents and drug targets in cancer and the SARS-CoV-2 spike that drives cell infection and immune invasion by variants and is the main component of most COVID-19 vaccines were also subjects of in-depth study. The results from this part help inform future research in these areas.
Data: CORDIS, © European Union
Project objective
Proteins are dynamic entities that undergo many structural transitions and fluctuations, which are essential to their biological functions. We, therefore, need continuous descriptions of protein conformational space in the form of energy landscapes in order to properly understand their mechanisms of action. This is now becoming possible through the use of hybrid methods, which combine computational biophysics with experimental structural biology and overcome the limitations of either approach alone. In this proposal, we present a new hybrid methodology that leverages recent innovations in cryo-electron microscopy image analysis to examine continuous dynamics and free energy landscapes of large, multi-domain proteins, which are not achievable with existing methods. Our novel interdisciplinary pipeline will involve the use of efficient coarse-grained representations of proteins from computational biophysics coupled with sophisticated image processing tools including 3D reconstruction, classification, and dimensionality reduction. The specific objective is to extract reaction coordinates from 3D class averages and use them to generate conformational landscapes onto which the raw 2D images can be mapped. The resulting free energy landscapes will reveal all conformational states with physiological relevance and the preferred transition pathways, which can be analysed further using molecular dynamics simulations. We will apply our pipeline to ionotropic glutamate receptors, which are tetrameric ligand-gated ion channels with large, dynamic, multi-domain architectures that are critical to synaptic transmission and plasticity in the mammalian central nervous system. We expect our results to be of great benefit to the broad structural biology community and to be instrumental in understanding brain physiology and designing treatments for a wide range of diseases.
Original text from CORDIS.
Participants
- AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS · MadridCoordinatorSpain
Links
Data: CORDIS, © European Union