Waldemar Kulig

Associate Professor (Docent), University Lecturer, PhD in theoretical chemistry

In my research, I explore the molecular mechanisms that govern life at the membrane interface using advanced computer simulations. I am particularly interested in biological processes where membranes play a central role – such as cellular signaling, membrane trafficking, protein–lipid interactions, and the effects of oxidative stress. My work combines atomistic and coarse-grained molecular dynamics simulations to investigate how lipid composition, sterols, and small molecules influence membrane properties and protein function. I also study the molecular underpinnings of drug delivery and nanoparticle formation at biological and synthetic surfaces, bridging biophysics and nanomedicine. Through close integration of simulations with experiments, I aim to uncover how dynamic molecular interactions translate into function in complex biological environments.



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 & Functional Surfaces

Can we make biomaterials do more than just support tissue? What if they could deliver drugs exactly where they're needed, right from the surface?

Can we make biomaterials do more than just support tissue? What if they could deliver drugs exactly where they're needed, right from the surface? Research in biomaterials is rapidly evolving toward site-specific drug delivery, offering targeted therapeutic action while minimizing side effects. From orthopedic implants to contraceptive devices, implantable systems are being designed to release drugs precisely where and when they’re needed. However, challenges remain in integrating drug carriers directly onto material surfaces due to the diversity of biomaterials and their interaction with the body. As a result, only a few such systems are in clinical use today. Ongoing research focuses on functionalizing these surfaces to allow seamless embedding of bioactive molecule nanoparticles, paving the way for smarter, more effective therapeutic materials.

Oxidative Stress

What if aging and disease were driven by a buildup of reactive molecules? Could understanding oxidative stress help us slow them down?

What if aging and disease were driven by a buildup of reactive molecules? Could understanding oxidative stress help us slow them down? Oxidative stress, caused by the accumulation of reactive oxygen species (ROS), plays a central role in aging and many diseases — including cancer, diabetes, Alzheimer’s, and cystic fibrosis. While our cells have evolved both enzymatic and non-enzymatic defense systems to neutralize ROS, these defenses aren’t always enough. The imbalance between ROS production and antioxidant defenses leads to cellular damage that accumulates over time. In this project, we explore the molecular mechanisms behind oxidative stress at the cellular level, aiming to shed light on its role in age-related decline and disease progression.

G Protein-Coupled Receptors

How do cells sense their environment and decide how to respond? G protein-coupled receptors (GPCRs) are at the heart of this molecular communication.

How do cells sense their environment and decide how to respond? G protein-coupled receptors (GPCRs) are at the heart of this molecular communication. GPCRs form a vast and versatile family of cell surface receptors that detect external signals — ranging from light and odors to hormones and neurotransmitters — and convert them into specific cellular responses. These receptors are essential for many physiological processes, including vision, smell, taste, neural signaling, cardiovascular regulation, and reproduction. Unsurprisingly, GPCRs are the targets of 30–40% of all currently approved drugs. Despite their central role in biology and medicine, the precise molecular mechanisms by which GPCRs initiate and propagate signals remain incompletely understood. In this project, we investigate GPCR signal transduction at the atomistic level, using molecular simulations to uncover how structural changes in the receptor translate extracellular cues into intracellular action.

Lung Surfactant

Every breath you take depends on an extraordinary biological interface: the pulmonary surfactant. But how does it actually work?

Every breath you take depends on an extraordinary biological interface: the pulmonary surfactant. But how does it actually work? Oxygen transport in the lungs begins in the alveoli — tiny air sacs where gas exchange occurs — and relies on the pulmonary surfactant (PSurf), a thin lipid-protein layer that lines the alveolar surface. This surfactant is essential not only for efficient oxygen diffusion into the bloodstream but also for preventing alveolar collapse during breathing. Despite its vital role, the molecular mechanisms by which PSurf supports oxygen transport remain poorly understood. Deficiency or malfunction of this system leads to life-threatening respiratory disorders such as neonatal and acute respiratory distress syndromes, cystic fibrosis, pneumonia, and bronchiolitis. In this project, we explore the physical and molecular principles that govern the function of pulmonary surfactant, aiming to uncover how this remarkable biological material makes breathing possible.

Protein-Lipid Interactions

Proteins and lipids team up in complex ways that are essential for life, yet the details of their interaction remain a mystery.

Proteins and lipids team up in complex ways that are essential for life, yet the details of their interaction remain a mystery. Cell membranes are dynamic structures where lipids and proteins closely interact to regulate key biological processes, from signaling and transport to membrane integrity and cellular communication. These protein-lipid interactions shape the membrane’s architecture and influence how cells respond to their environment. Despite their importance, the atomistic mechanisms driving these interactions are still not fully understood. Disruptions in protein-lipid interplay are linked to numerous diseases, including neurodegeneration and metabolic disorders. Our research aims to unravel the molecular details of how proteins and lipids cooperate within membranes, shedding light on the fundamental principles that govern cellular function and opening doors for novel therapeutic strategies.

Methods Development

Cutting-edge science demands cutting-edge tools — developing new computational methods is at the heart of breakthroughs.

Cutting-edge science demands cutting-edge tools — developing new computational methods is at the heart of breakthroughs. Innovative simulation techniques, including the development and refinement of molecular force fields, enable us to explore biological systems with unprecedented accuracy and realism. Traditional approaches often struggle to capture the complexity of biomolecular interactions and dynamics. By advancing force fields and other computational methods, we push the boundaries of molecular modeling and deepen our understanding of biological processes. These tools not only empower our research on membranes, proteins, and nanoparticles but also provide valuable resources for the broader scientific community, accelerating discoveries across biophysics and molecular biology.

Latests Publications.

Unraveling the GM1 Specificity of Galectin-1 Binding to Lipid Membranes

ACS Bio & Med Chem Au, 5 (2025) 415–426 (DOI: 10.1021/acsbiomedchemau.5c00040)

Galectin-1 (Gal-1) is a galactose-binding protein involved in various cellular functions. Gal-1’s activity has been suggested to be connected to two molecular concepts, which are, however, lacking experimental proof: a) enhanced binding affinity of Gal-1 toward membranes containing monosialotetrahexosylganglioside (GM1) over disialoganglioside GD1a and b) cross-linking of GM1’s by homodimers of Gal-1. Here, we provide evidence about the specificity and the nature of the interaction of Gal-1 with model membranes containing GM1 or GD1a, employing a broad panel of fluorescence-based and label-free experimental techniques, complemented by atomistic biomolecular simulations.

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Unraveling The Effect of Water And Ethanol On Ibuprofen Nanoparticles Formation

Journal of Molecular Liquids, 428 (2025) 127563 (DOI: 10.1016/j.molliq.2025.127563)

In this study, we investigate how water and ethanol affect the formation of ibuprofen sodium salt nanoparticles. Both experimental data and simulations indicate that ethanol is a superior solvent for ibuprofen nanosizing. These findings provide a rational basis for selecting solvents in drug formulation and offer a broader perspective for optimizing drug delivery applications.

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Assessing Vitamin E Acetate As a Proxy For e-Cigarette Additives In a Realistic Pulmonary Surfactant Model

Scientific Reports, 14 (2024) 23805 (DOI: 10.1038/s41598-024-75301-8)

Additives in vaping products, such as flavors, preservatives, or thickening agents, are commonly used to enhance user experience. Among these, Vitamin E acetate (VEA) was initially thought to be harmless but has been implicated as the primary cause of e-cigarette or vaping product use-associated lung injury, a serious lung disease. In our study, VEA serves as a proxy for other e-cigarette additives. To explore its harmful effects, we developed an exposure system to subject a pulmonary surfactant (PSurf) model to VEA-rich vapor. Through detailed analysis and atomic-level simulations, we found that VEA tends to cluster into aggregates on the PSurf surface, inducing deformations and weakening its essential elastic properties, critical for respiratory cycle function.

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Insights Into Short Chain Polyethylene Penetration of Phospholipid Bilayers Via Atomistic Molecular Dynamics Simulations

Biochimica et Biophysica Acta (BBA) - Biomembranes, 1866 (2024) 184327 (DOI: 10.1016/j.bbamem.2024.184327)

The escalation of global plastic production, reaching an annual output of 400 million tons, has significantly intensified concerns regarding plastic waste management. This has been exacerbated by improper recycling and disposal practices, contributing to the impending crisis of plastic pollution. Predictions indicate that by 2025, the environment will bear the burden of over ten billion metric tons of accumulated plastic waste. This situation has led to the concerning release of microplastics and nanoplastics (NPs) into the environment as plastic materials degrade, thereby posing risks to both ecosystems and human health. In this study, we leverage all-atom MD simulations to delve into the interactions between lipid bilayers and polyethylene (PETH) chains of varying lengths.

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Revealing The Key Structural Features Promoting The Helical Conformation In Algal Polysaccharide Carrageenan In Solution

Carbohydrate Polymers, 331 (2024) 121901 (DOI: 10.1016/j.carbpol.2024.121901)

Carrageenans are industrially important polysaccharides with tunable viscoelastic and gelation properties. The function of polysaccharide depends on its conformation and chemical composition. However, the solution conformations of carrageenans are highly debated, and the structure-function relationship remains elusive. Here, we have studied the intrinsic conformational behavior of a series of carrageenan hexamers in solution, using extensive all-atom classical MD and enhanced sampling.

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Zika Virus prM Protein Contains Cholesterol Binding Motifs Required For Virus Entry And Assembly

Nature Communications, 14 (2023) 7344 (DOI: 10.1038/s41467-023-42985-x)

For successful infection of host cells and virion production, enveloped viruses, including Zika virus (ZIKV), extensively rely on cellular lipids. However, how virus protein–lipid interactions contribute to the viral life cycle remains unclear. Here, we employ a chemo-proteomics approach with a bifunctional cholesterol probe and show that cholesterol is closely associated with the ZIKV structural protein prM. Bioinformatic analyses, reverse genetics alongside with photoaffinity labeling assays, and atomistic molecular dynamics simulations identified two functional cholesterol binding motifs within the prM transmembrane domain.

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In Vitro and In Silico Studies of Functionalized Polyurethane Surfaces toward Understanding Biologically Relevant Interactions

ACS Biomaterials Science & Engineering, 9 (2023) 6112–6122 (DOI: 10.1021/acsbiomaterials.3c01367)

The solid–aqueous boundary formed upon biomaterial implantation provides a playground for most biochemical reactions and physiological processes involved in implant–host interactions. Therefore, for biomaterial development, optimization, and application, it is essential to understand the biomaterial–water interface in depth. In this study, oxygen plasma-functionalized polyurethane surfaces that can be successfully utilized in contact with the tissue of the respiratory system were prepared and investigated. The influence of plasma treatment on the physicochemical properties of polyurethane was investigated by atomic force microscopy, attenuated total reflection infrared spectroscopy, differential thermal analysis, X-ray photoelectron spectroscopy, secondary ion mass spectrometry, and contact angle measurements, supplemented with biological tests using the A549 cell line and two bacteria strains (Staphylococcus aureus and Pseudomonas aeruginosa).

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How Neuromembrane Lipids Modulate Membrane Proteins: Insights from G-Protein-Coupled Receptors (GPCRs) and Receptor Tyrosine Kinases (RTKs)

Cold Spring Harbor Perspectives in Biology, 15 (2023) a041419 (DOI: 10.1101/cshperspect.a041419)

Lipids play a diverse and critical role in cellular processes in all tissues. The unique lipid composition of nerve membranes is particularly interesting because it contains, among other things, polyunsaturated lipids, such as docosahexaenoic acid, which the body only gets through the diet. The crucial role of lipids in neurological processes, especially in receptor-mediated cell signaling, is emphasized by the fact that in many neuropathological diseases there are significant deviations in the lipid composition of nerve membranes compared to healthy individuals. In this review, we focus on two major protein families: G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) and discuss how lipids affect their function in neuronal membranes, elucidating the basic mechanisms underlying neuronal function and dysfunction.

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Deciphering Lipid Arrangement in Phosphatidylserine/Phosphatidylcholine Mixed Membranes: Simulations and Experiments

Langmiur, 39 (2023) 18995–19007 (DOI: 10.1021/acs.langmuir.3c03061)

Phosphatidylserine (PS) exposure on the plasma membrane is crucial for many cellular processes including apoptotic cell recognition, blood clotting regulation, cellular signaling, and intercellular interactions. In this study, we investigated the arrangement of PS headgroups in mixed PS/phosphatidylcholine (PC) bilayers, serving as a simplified model of the outer leaflets of mammalian cell plasma membranes. Combining atomistic-scale molecular dynamics (MD) simulations with Langmuir monolayer experiments, we unraveled the mutual miscibility of POPC and POPS lipids and the intricate intermolecular interactions inherent to these membranes as well as the disparities in position and orientation of PC and PS headgroups.

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

ACS Applied Nano Materials, 6 (2023) 4271–4278 (DOI: 10.1021/acsanm.2c05332)

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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Teaching & Outreach.