Modeling of proteins with low-resolution experimental data

NAISS 2023/3-27


NAISS Large Compute

Principal Investigator:

Erik Lindahl


Kungliga Tekniska högskolan

Start Date:


End Date:


Primary Classification:

10603: Biophysics

Secondary Classification:

10602: Biochemistry and Molecular Biology

Tertiary Classification:

10407: Theoretical Chemistry



The purpose of our work is to understand how channels and other proteins move between conformations, how large motions and allosteric modulation are induced by small external factors (e.g. ligand binding, changes in membrane potential, or lipid composition), and to develop techniques to combine several sources of experimental data such as cryo-EM, electrophysiology and neutron scattering with bioinformatics and simulation to create models of the entire ensemble of structural and functional states for ion channels and transporters. Our computational work supported by NAISS enables us to build atomic-resolution models to study features not readily available in experiments, such as transitions between states and finding new ways to use low-resolution experimental data. Our primary model system is the pentameric ligand-gated ion channels responsible for mediating chemical singling across the synapse in the nervous system, as well as their bacterial homologs. While we increasingly have structural data for these channels, we still do not understand the molecular mechanism of gating, and the desensitised state all channels end up in shortly after activation is still almost entirely uncharacterised. Here, we propose to use molecular dynamics simulations in combination with Markov State Models to determine both the free energy landscape of channel activation, as well as the kinetics of transitions between states, and how this is changed by allosteric modulation. We will similarly use simulations to explain the differences in molecular interactions between positive (enhancing) and negative (dampening) allosteric modulators, to identify state-specific binding, and understand the interplay between lipid and small-molecule modulation of ion channels. We also combine both our MSM sampling and density fitting codes with new conformations predicted from AlphaFold, based on the idea that AF2 frequently generates a whole range of candidate clusters - and at least in a few cases lower-ranking clusters appear to have corresponded to alternative conformations, which are enabling us to model conformational transitions without having to resort to classical molecular dynamics simulations. An important part of our work is that we are able to combine cryo-EM data with molecular dynamics, which has enabled several studies with deep mechanistic insight about gating and modulation. In addition to this, we have just started a new NSF-funded joint center for "Quantitative Cell Biology" together with UIUC, where we aim to integrate tomography data with MINFLUX superresolution microscopy and build coarse-grained models of entire minimal cells. While this should enable a few showcases about the largest simulations to date, and hopefully stellar visualizations together with the visualization center in Norrköping, our long-term goal is to use it to parametrize continuum models in the "Lattice Microbes" framework together with Zan Schulten's team at UIUC, which if successful will enable us to use computational tools to make predictions about specific cellular states resolved spatially and temporally over hours to days.