Skip to main content
Login | Suomeksi | På svenska | In English

Browsing by Subject "Functional sampling"

Sort by: Order: Results:

  • Functional Sampling Tool: A Novel Method to Enhance Sampling in Molecular Dynamics Simulations : with applications to NMDAR dynamics 
    Paajanen, Santeri (2022)
    NMDA receptors are ionotropic glutamate receptors (iGluRs), tetrameric proteins, mediating synaptic transmission in the brain and the whole nervous system. Together with another type of iGluRs, AMPA receptors, they are considered essential for neuronal plasticity and memory. Understanding their dynamics and different kinetics is vital for studying various neurological diseases. The relatively slow dynamics, where the time scales of related processes range up to hundreds of milliseconds, make studying them with Molecular Dynamics (MD) simulations challenging. We developed the Functional Sampling Tool (FST), a novel method for enhancing the sampling of a function of interest. Compared to existing enhanced sampling schemes it strikes a balance between generality and simplicity, minimising the need of user input, while allowing for maximal customisability. Using FST, we studied two processes of the NMDA receptor. By keeping all four ligands bound we simulated a desensitisation pathway, and by removing all four we simulated an inactivation pathway. The tool sampled both, giving a good distribution between open and closed states. The tool also allowed us to change the function in the middle of sampling. With the new function we were able to produce more data, focusing on a certain value range.
  • Lipid-Driven Basal Activity of the Beta-2 Adrenergic Receptor 
    Eurasto, Felix (2024)
    G protein-coupled receptors (GPCRs) constitute the largest family of receptors in humans. They are involved in the regulation of major biological processes including sight, taste, and mood. Due to their prevalence in the human body and involvement in such a wide range of tasks, GPCRs are medically extremely important. GPCRs are cell-surface receptors, responsible for conveying biological messages from the extracel- lular domain to the cytoplasmic region. As such, GPCRs are constantly interacting with the lipids of the cell membrane. These interactions are thought to mediate the activation behaviour of the GPCRs, although the exact nature of these effects is often unknown. The beta-2 adrenergic receptor (β2AR) is a class-A GPCR, whose native ligand is adrenaline. It plays a crucial role in the inactivation of the sympathetic nervous system to trigger the fight-or-flight response. Many GPCRs exhibit basal activity. That is, these receptors can activate even in the absence of an activating ligand. β2AR is one of these GPCRs. The specific cause and mechanism of basal activity are often unknown and, as of the start of the project presented in this thesis, were undetermined for β2AR. We used high-throughput fully atomistic molecular dynamics (MD) simulations coupled with ma- chine learning (ML) methods to ascertain specific interactions between a highly conserved aspartate residue of β2AR and phosphatidylcholine (PC) lipids that stabilize the active state of β2AR. We also found that cholesterol plays a role in mediating these interactions. These results shed light on the effect of the lipid composition of one’s cell membranes, and by extension one’s lipid diet, on the activation behaviour of β2AR, a medically extremely relevant receptor.

Yhteystiedot

HELSINGIN YLIOPISTO