Research description
The workings of living systems are the result of the rich physics that emerges from their nanoscopic building blocks. This intriguing nanoscopic world is becoming increasingly accessible to quantitative observation and nanomanipulation techniques. We aim to explore and exploit the physics of biomolecular systems such as DNA and molecular motors, and their interplay with synthetic systems using quantitative experimental analysis and modeling at the single-molecule level. In our research endeavors we develop innovative biophysical research methodologies and push the limits of quantitative experimental analysis and (nanoscale) imaging methods.
Research Interests
Physics of DNA & small molecule-DNA interactions: DNA intercalation
In living cells, the structure of DNA is continuously impacted by mechanical and biochemical cues. DNA intercalators are small (synthetic) molecules that can bind and mechanically extend and unwind DNA. When bound to DNA, intercalators are excellent fluorescent probes and intercalation also plays a role in chemotherapeutic treatments to inhibit DNA-associated processes. We use DNA intercalation as model system to explore small-molecule DNA-interactions and analyze the structural transitions of DNA. We exploit our understanding of this model system to develop new biophysical methods based on (controllable) DNA intercalation.
Physics of ice binding proteins and crystal growth
Growth of ice crystals can induce critical damage to soft condensed matter systems such as living tissue and cells. Many lifeforms produce ice-binding proteins (IBPs) for protection against frost-damage. We aim to understand how IBPs can function as such remarkable cryoprotectants. Although models exist that relate IBP activity to pinning of advancing ice planes, numerous open questions regarding the underlying physics remain. We search for answers to these mechanistic questions by probing IBP activity at the molecular length scales where IBPs act.
Single-molecule analysis of DNA transactions
Our knowledge of the building blocks of life has advanced significantly through the ongoing development of single-molecule biophysical methods. We push the limits of our ability to explore the biomolecular world by developing new and powerful single-molecule approaches. Such development is done with specific biological questions or experimental challenges in mind. The combination of optical trapping and (super-resolution) fluorescence microscopy is for example particularly powerful for quantitative analyses of biomolecular systems such as DNA-protein complexes. In several collaborations we have exploited the use of optical tweezers and fluorescence microscopy to analyze the molecular mechanisms of DNA transactions. This includes analysis of DNA replication, DNA compaction, DNA repair and DNA transcription. Current topics include the interface of DNA with synthetic (photoactivated) compounds and motors.
Selected publications
- Nonlinear mechanics of human mitotic chromosomes, Meijering AEC, Sarlos K, Nielsen CF, Witt H, Harju J, Kerklingh E, Haasnoot GH, Bizard AH, Heller I, Broedersz CP, Liu Y, Peterman EJG, Hickson ID, Wuite GJL, Nature, 605 545 (2022)
- Imaging unlabeled proteins on DNA with super-resolution, Meijering AEC, Biebricher AS, Peterman EJG, Wuite GJL, Heller I, Nucleic acids research, 48 (6) e34 (2020)
- Single-molecule polarization microscopy of DNA intercalators sheds light on the structure of S-DNA, Backer AS, Biebricher AS, King GA, Wuite GJL*, Heller I*, Peterman EJG*, Science Advances, 5 (3) eaav1083 (2019)
- Hyperstretching DNA, Schakenraad K, Biebricher AS, Sebregts M, ten Bensel B, Peterman EJG, Wuite GJL, Heller I*, Storm C*, van der Schoot P*, Nature communications, 8 2197 (2017)
- Single-molecule observation of DNA compaction by meiotic protein SYCP3, Syrjanen, JL*, Heller I*, Candelli A, Davies OR, Peterman EJG, Wuite GJL, Pellegrini L, eLife, (6) e22582 (2017)
- Sliding sleeves of XRCC4–XLF bridge DNA and connect fragments of broken DNA, Brouwer I*, Sitters, G*, Candelli A, Heerema SJ, Heller I, de Melo AJ, Zhang H, Normanno D, Modesti M, Peterman EJG, Wuite GJL, Nature, 535 566 (2016)
- The impact of DNA intercalators on DNA and DNA-processing enzymes elucidated through force-dependent binding kinetics, Biebricher AS*, Heller I*, Roijmans RFH, Hoekstra TP, Peterman EJG, Wuite GJL, Nature communications, 6 7304 (2015)
- Optical tweezers analysis of DNA-protein complexes, Heller I, Hoekstra TP, King GA, Peterman EJG, Wuite GJL, Chemical Reviews, 114 3087 (2014)
- STED nanoscopy combined with optical tweezers reveals protein dynamics on densely covered DNA, Heller I, Sitters G, Broekmans OD, Farge G, Menges C, Wende W, Hell SW, Peterman EJG, Wuite GJL, Nature Methods, 10 910 (2013)
- Influence of electrolyte composition on liquid-gated carbon-nanotube and graphene transistors, Heller I, Chatoor S, Männik J, Zevenbergen MAG, Dekker C, Lemay SG, J. Am. Chem. Soc., 132 17149 (2010)
- Identifying the mechanism of biosensing with carbon nanotube transistors, Heller I, Janssens AM, Männik J, Minot ED, Lemay SG, Dekker C, Nano Letters, 8 591 (2008)
