Proteins and their function

How does the ATP sensitive potassium channel work?

Human well-being depends on good health. The metabolism of 51 amino acid (aa) protein hormone insulin is an important factor in maintaining health. ATP-sensitive potassium channels (KATP) play a key role in insulin secretion from pancreatic beta-cells. They close in response to a change in the ATP/ADP ratio and stop the K- outflow, leading to insulin release. Normally this happens when the blood glucose revel rises. Malfunctioning of KATP leads to diabetes.

Despite its enormous physiological role, the mechanism of closing/opening of KATP is not known yet. Fortunately, since 2017 the KATP structure is known. It is a huge complex (~8000aa) composed of four Kir6.2 subunits and four sulfonylurea receptor moieties. This discovery opens a way to model the KATP channel gating. The complexity of KATP system calls for methods able to monitor structural changes. A standard approach is molecular dynamics, it may help to understand “bold-and-nuts” of opening/closing KATP channels. By performing extensive computer modeling of the whole KATP complex we hope to move towards understanding mechanisms of the KATP channel gating, and developing better antidiabetic drugs.

K. Walczewska-Szewc, W. Nowak
Photo-Switchable Sulfonylureas Binding to ATP-Sensitive Potassium Channel Reveal the Mechanism of Light-Controlled Insulin Release
J. Phys. Chem. B 125, 13111-13121 (2021)
DOI

K. Walczewska-Szewc, and W. Nowak
Structural Determinants of Insulin Release: Disordered N-Terminal Tail of Kir6. 2 Affects Potassium Channel Dynamics through Interactions with Sulfonylurea Binding Region in a SUR1 Partner
J. Phys. Chem. B 124, 6198 (2020)
DOI

K. Walczewska-Szewc, and W. Nowak
Spacial models of malfunctioned protein complexes help to elucidate signal transduction critical for insulin release
Biosystems 177, 48 (2019)
DOI

Prolyl oligopeptidase (PREP) and its function in neurodegenerative disorders

The formation of extended misfolded protein aggregates is one of the main reasons for neuronal malfunction and, eventually, brain damage in many neurodegenerative diseases. In Parkinson’s disease alpha-synucleins are implicated in the accumulation of the aggregates. The origin of such aggregation is not yet known, however, there is a compelling evidence that it can be reduced by inhibition of prolyl oligopeptidase (PREP). This effect cannot be simply related to the inhibition of the catalytic function of the enzyme, as not all PREP inhibitors stop the alpha-synuclein aggregation.

Finding differences in the dynamics of the enzyme inhibited with diverse compounds would allow us to pinpoint the regions of the protein involved in the interaction between PREP and alpha-synuclein. Here, we study the action of three PREP inhibitors, each of which affects alphasynuclein aggregation to different extent. Using molecular dynamics modelling, we determine molecular mechanisms underlying the PREP inhibition and identify structural differences in each inhibitor-PREP system. We suggest that even subtle differences in the dynamics of the enzyme affect its interactions with alpha-synucleins. Thus, identification of these regions may be crucial in preventing formation of alpha-synuclein aggregates.

K. Walczewska-Szewc, J. Rydzewski, A. Lewkowicz
Inhibition-mediated changes in prolyl oligopeptidase dynamics possibly related to α-synuclein aggregation
Phys Chem Chem Phys, 24, 4366-4373 (2022)
DOI

G-protein coupled receptors and signal transduction

Mosquitos are the primary vectors of diseases that affect roughly 700 million and kill a million people each year. Malaria remains a major killer of children under five years old, taking the life of a child every two minutes. Unfortunately, the most commonly used repellents (i.e. DEET) lose their activity as mosquitoes become resistant. Moreover, they are found to be neurotoxic for humans, especially for children. Therefore, there is a high need for new generation of mosquito repellents.

G-protein coupled receptors (GPCRs) play a crucial role in signal transduction and are target of 30-50% of all modern drugs. These receptors play a key role in activity of both human and insect neuronal system. Recent studies indicate that one of repellents mode of action is modulation of GPCRs but the precise mechanism remains obscure.

Using molecular dynamics and docking we investigate the conformational changes in GPCRs, in response to ligands binding. Knowing the molecular basis of these changes will facilitate finding compounds that would serve as selective malaria vectors repellents having no side effects in human.

#<h2> Nanomechanics of synaptic proteins <h2>

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