Proteins and their function

How do ATP-sensitive potassium channels work in different tissues?

ATP-sensitive potassium (KATP) channels play a crucial role in coupling cellular metabolism to electrical activity in many tissues, including pancreatic β-cells, the cardiovascular system, and vascular smooth muscle. One of their best-known functions is the regulation of insulin secretion, where an increase in the intracellular ATP/ADP ratio leads to KATP channel closure, membrane depolarization, and insulin release. In cardiac and vascular tissues, KATP channels contribute to the regulation of excitability, contractility, and vascular tone, allowing cells to adapt to metabolic stress. Malfunction of these channels is linked not only to metabolic disorders such as diabetes, but also to cardiovascular diseases.

Despite their enormous physiological importance, the molecular mechanisms governing KATP channel opening and closing are still not fully understood. Since 2017, high-resolution structures of the KATP channel have become available. The channel is a large hetero-octameric complex (~8000 amino acids), composed of four Kir6.2 subunits and four sulfonylurea receptor (SUR) subunits. These structures opened the door to detailed computational studies of KATP channel gating and regulation.

My research focuses on understanding the structural dynamics of KATP channels across different tissues, with particular emphasis on vascular KATP channels and isoform-specific effects. We aim to explain how selective ligands modulate distinct KATP isoforms and why certain compounds act in a tissue-dependent manner. An important aspect of this work is the role of intrinsically disordered regions (IDRs), which are increasingly recognized as key regulators of channel function, ligand sensitivity, and protein–protein interactions.

To address these questions, we use a combination of computational approaches, including all-atom and coarse-grained molecular dynamics simulations, as well as enhanced sampling techniques. By integrating structural data with advanced simulation methods, we seek to uncover the dynamic mechanisms underlying KATP channel regulation and to support the rational design of more selective therapeutics targeting metabolic and cardiovascular diseases.

A. ElSheikh, C.M. Driggers, H.H. Truong, Z. Yang, J. Allen, N. Henriksen, K. Walczewska-Szewc, S-L Shyng AI-Based Discovery and CryoEM Structural Elucidation of a KATP Channel Pharmacochaperone
eLife 13:RP103159 (2024)
DOI

K. Walczewska-Szewc, W. Nowak
Structural Insights into ATP-Sensitive Potassium Channel Mechanics: A Role of Intrinsically Disordered Regions
JCIM, 63, 1806-1818 (2023)
DOI

D. Criveanu, C.A. Bergqvist, D. Larhammar,K. Walczewska-Szewc Identification of a new Kir6 potassium channel and comparison of properties of Kir6 subtypes by structural modelling and molecular dynamics
Int. J. Biol. Macromol 247, 125771 (2023)
DOI

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
Decoding dissociation pathways of ligands in prolyl oligopeptidase
Phys Chem Chem Phys, 28(1):829-840 (2026)
DOI

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>

#<h2> Hydrogen bond in alpha-helices <h2>

#<h2> P2X7 as a promising target in therapy of glioma <h2>