Waldemar Kulig

University Lecturer, PhD in theoretical chemistry

In my research, I try to understand molecular mechanisms of various biological processes using computer simulations. In particular, I am interested in key processes connected with biological membranes, such as cellular signalling and trafficking, the effect of the oxidative stress, protein-lipid interactions, and drug delivery.



Affiliation:

Department of Physics
Exactum Building, office C117
University of Helsinki
P.O. Box 68 (Pietari Kalmin katu 5)
FI-00014 Helsinki, Finland


waldemar.kulig@helsinki.fi

Research.

Biomaterials

Biomaterial research is advancing with a focus on controlled site-specific drug delivery, offering a promising alternative to traditional administration methods. Site-specific, controlled drug delivery is especially desirable to elicit a localized therapeutic effect.

Biomaterial research is advancing with a focus on controlled site-specific drug delivery, offering a promising alternative to traditional administration methods. From orthopedic implants to contraceptive rings, these implantable drug delivery devices precisely target therapeutic effects while minimizing systemic drug levels. Challenges persist in applying carriers directly to biomaterial surfaces due to various material properties and destination points within the body. As a result, only a limited number of drug delivery systems are currently utilized in clinical settings, prompting further research to broaden their applicability across different classes of biomaterials. Ongoing efforts aim to develop innovative approaches for functionalizing biomaterial surfaces, facilitating the immediate embedment of bioactive molecule nanoparticles. These advancements hold the potential to enhance therapeutic outcomes in various medical applications.

Oxidative Stress

Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of the damages induced by reactive oxygen species.

Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of the damages induced by reactive oxygen species (ROS). For organisms living in an aerobic environment, exposure to reactive oxygen species is unavoidable. A number of cellular defense systems have evolved to eliminate the accumulation of ROS. These include various non-enzymatic molecules (glutathione, vitamins A, C, and E, and flavonoids) as well as enzymatic scavengers of ROS (superoxide dismutases, catalase, and glutathione peroxide). Unfortunately, these mechanisms are not always efficient enough to prevent the production of ROS, resulting in so-called oxidative stress. In cells, oxidative stress is involved in diseases such as cancer, cystic fibrosis, type-2 diabetes, Alzheimer’s disease, and it is also a major factor of ageing. In this project, we try to understand the molecular mechanisms of oxidative stress on a cellular level.

G Protein-Coupled Receptors

Signal transduction by G protein-coupled receptors (GPCRs) is fundamental for most physiological processes, spanning from vision and smell to neurological and cardiovascular functions, thus, making the GPCR family a major target for therapeutic intervention.

G protein-coupled receptors (GPCRs) form an important family of cell surface receptors that respond to an array of diverse ligands and transduce extracellular signals into intracellular responses. Due to the major involvement of GPCRs in regulating physiological processes, these receptors are of great medical importance as they are targeted by 30-40% of the currently marketed drugs. Signal transduction by GPCRs is fundamental for most physiological processes, spanning from vision, smell and taste to neurological, cardiovascular, and reproductive functions. However, molecular mechanism, by which the receptor propagates the signal, remains unknown. In this project, we try to understand the atomistic picture of the signal transduction facilitated by GPCRs.

Lung Surfactant

The main function of lungs is to transport oxygen from alveoli through the pulmonary surfactant to blood circulation, where it is used together with glucose in cellular respiration to produce ATP, the main source of energy in cells.

The main function of lungs is to transport oxygen from alveoli (tiny air sacs in the lungs) through the pulmonary surfactant to blood circulation, where it is used together with glucose in cellular respiration to produce ATP, the main source of energy in cells. As we would not stay alive without oxygen, it is crucial to understand how oxygen and other molecules are taken into cells. The outstanding unsolved question is how the pulmonary surfactant (PSurf) works. PSurf is crucial for oxygen transport and hence for survival. The lack, deficiency, or alteration in the composition of PSurf is the cause of severe respiratory disorders that are mostly lethal, such as neonatal respiratory distress syndrome, the acute respiratory distress syndrome, cystic fibrosis, pneumonia, bronchiolitis, and many more. The aim of this project is to understand physical mechanisms governing the function of pulmonary surfactant.

Latests Publications.

Sonochemical Formation of Fluorouracil Nanoparticles: Toward Controlled Drug Delivery from Polymeric Surfaces

ACS Applied Nano Materials, 6 (2023) 4271–4278

The biomaterial surface can be essentially upgraded with the therapeutic function by the introduction of controlled, local elution of biologically active molecules. The use of ultrasonic-assisted formation of nanoparticles with controlled size and morphology can be readily utilized for such functionalization. In this study, the synthesis route for the generation of nanoparticles of fluorouracil, the bioactive molecule used in anticancer therapy, was reported. The tandem of experimental (TEM, NTA, ATR-IR) and computational (MD simulations) approaches allowed us to obtain a molecular-level picture of the cavitation bubble interface where the enrichment of fluorouracil molecules takes place. Here, we revealed that the bubble interface plays a key role in the prearrangement of drug and solvent molecules, initiating the formation of nanoparticles’ seeds.

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Mcl-1 and Bok Transmembrane Domains: Unexpected Players in the Modulation of Apoptosis

Proceedings of the National Academy of Sciences of the United States of America, 117 (2020) 27980-27988

The Bcl-2 protein family comprises both pro- and antiapoptotic members that control the permeabilization of the mitochondrial outer membrane, a crucial step in the modulation of apoptosis. Recent research has demonstrated that the carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 protein family members can modulate apoptosis; however, the transmembrane interactome of the antiapoptotic protein Mcl-1 remains largely unexplored. Here, we demonstrate that the Mcl-1 TMD forms homooligomers in the mitochondrial membrane, competes with full-length Mcl-1 protein with regards to its antiapoptotic function, and induces cell death in a Bok-dependent manner.

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Rigorous Computational Study Reveals What Docking Overlooks: Double Trouble From Membrane Association in Protein Kinase C Modulators

Journal of Chemical Information and Modeling, 60 (2020) 5624-5633

In this work, we aimed to determine the cause of the greatly diminished binding of the pyrimidine analogs of the isophthalate derivatives to the C1 domain of PKC. We achieved this through examination of two specific compounds, HMI-1a3 and PYR-1gP, in a multi-faceted study utilizing comprehensive molecular modeling, electronic structure calculations and NMR measurements.

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Tail-Oxidized Cholesterol Enhances Membrane Permeability for Small Solutes

Langmuir, 36 (2020) 10438–10447

Cholesterol renders mammalian cell membranes more compact by reducing the amount of voids in the membrane structure. Because of this, cholesterol is known to regulate the ability of cell membranes to prevent the permeation of water and water-soluble molecules through the membranes. Meanwhile, it is also known that even seemingly tiny modifications in the chemical structure of cholesterol can lead to notable changes in membrane properties. The question is, how significantly do these small changes in cholesterol structure affect the permeability barrier function of cell membranes?

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Functionalization of the Parylene C Surface Enhances the Nucleation of Calcium Phosphate: Combined Experimental and Molecular Dynamics Simulations Approach

ACS Applied Materials & Interfaces, 12 (2020) 12426–12435

Interactions at the solid–body fluid interfaces play a vital role in bone tissue formation at the implant surface. In this study, fully atomistic molecular dynamics simulations were performed to investigate interactions between the physiological components of body fluids and functionalized parylene C surface.

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Reduced Level of Docosahexaenoic Acid Shifts GPCR Neuroreceptors To Less Ordered Membrane Regions

PLOS Computational Biology, 15 (2019) e1007033 (DOI: 10.1371/journal.pcbi.1007033)

G protein-coupled receptors (GPCRs) control cellular signaling and responses. Many of these GPCRs are modulated by cholesterol and polyunsaturated fatty acids (PUFAs) which have been shown to co-exist with saturated lipids in ordered membrane domains. However, the lipid compositions of such domains extracted from the brain cortex tissue of individuals suffering from GPCR-associated neurological disorders show drastically lowered levels of PUFAs.

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Complex Behavior of Phosphatidylcholine–Phosphatidic Acid Bilayers and Monolayers: Effect of Acyl Chain Unsaturation

Langmuir, 35 (2019) 5944 (DOI: 10.1021/acs.langmuir.9b00381)

Phosphatidic acids (PAs) have many biological functions in biomembranes, e.g., they are involved in the proliferation, differentiation, and transformation of cells. Despite decades of research, the molecular understanding of how PAs affect the properties of biomembranes remains elusive.

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Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance

Chemical Reviews, 119 (2019) 5607 (DOI: 10.1021/acs.chemrev.8b00538)

Biological membranes are tricky to investigate. They are complex in terms of molecular composition and structure, functional over a wide range of time scales, and characterized by nonequilibrium conditions. Because of all of these features, simulations are a great technique to study biomembrane behavior.

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Bobbing of Oxysterols: Molecular Mechanism for Translocation of Tail-Oxidized Sterols Through Biological Membranes

The Journal of Physical Chemistry Letters, 9 (2018) 1118 (DOI: 10.1021/acs.jpclett.8b00211)

Translocation of sterols between cellular membrane leaflets is of key importance in membrane organization, dynamics, and signaling. We present a novel translocation mechanism that differs in a unique manner from the established ones. The bobbing mechanism identified here is demonstrated for tail-oxidized sterols, but is expected to be viable for any molecule containing two polar centers at the opposite sides of the molecule.

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How to Minimize Dye-Induced Perturbations While Studying Biomembrane Structure and Dynamics: PEG Linkers As a Rational Alternative

BBA-Biomembranes, 1860 (2018) 2436 (DOI: 10.1016/j.bbamem.2018.07.003)

Organic dye-tagged lipid analogs are essential for many fluorescence-based investigations of complex membrane structures, especially when using advanced microscopy approaches. However, lipid analogs may interfere with membrane structure and dynamics, and it is not obvious that the properties of lipid analogs would match those of non-labeled host lipids.

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Physiologically-Relevant Levels of Sphingomyelin, But Not GM1, Induces a β-Sheet-Rich Structure In The Amyloid-β(1-42) Monomer

BBA-Biomembranes, 1860 (2018) 1709 (DOI: 10.1016/j.bbamem.2018.03.026)

To resolve the contribution of ceramide-containing lipids to the aggregation of the amyloid-β protein into β-sheet rich toxic oligomers, we employed molecular dynamics simulations to study the effect of cholesterol-containing bilayers comprised of POPC and physiologically relevant concentrations of sphingomyelin, and the GM1 ganglioside.

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Cholesterol Protects The Oxidized Lipid Bilayer From Water Injury: An All-Atom Molecular Dynamics Study

Journal of Membrane Biology, 251 (2018) 521 (DOI: 10.1007/s00232-018-0028-9)

In an effort to delineate how cholesterol protects membrane structure under oxidative stress conditions, we monitored the changes to the structure of lipid bilayers comprising 30 mol% cholesterol and an increasing concentration of Class B oxidized 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) glycerophospholipids.

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The Role of Hydrophobic Mismatch in Transmembrane Helix Dimerization in Biological Membranes of Living Cells

Cell Stress, 1 (2017) 90 (DOI: 10.15698/cst2017.11.111)

Folding and packing of membrane proteins are highly influenced by the lipidic component of the membrane. Here, we explore how the hydrophobic mismatch (the difference between the hydrophobic span of a transmembrane protein region and the hydrophobic thickness of the lipid membrane around the protein) influences transmembrane helix packing in a cellular environment.

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Molecular Dynamics Insights Into Water-Parylene C Interface: Relevance of Oxygen Plasma Treatment for Biocompatibility

ACS Applied Materials & Interfaces, 9 (2017) 16685-16693 (DOI: 10.1021/acsami.7b03265)

Solid–water interfaces play a vital role in biomaterials science because they provide a natural playground for most biochemical reactions and physiological processes. In the study, fully atomistic molecular dynamics simulations were performed to investigate interactions between water molecules and several surfaces modeling for unmodified and modified parylene C surfaces.

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