Enzymes are typically studied in ensembles. Enzyme mechanism has traditionally been elucidated from biochemical and structural experiments that involve thousands or millions of molecules. Enzymes, however, are complex molecular machines that, when subjected to individual scrutiny, reveal features that cannot be ascertained from ensemble approaches. Single-molecule visualization and manipulation techniques are at the technological forefront of biological enquiry; these techniques can probe distances on the sub-nanometer (10-9 M) scale and forces on the piconewton (10-12 N) scale with millisecond temporal resolution. Dr. Neuman employs these techniques—including optical and magnetic tweezers and fluorescence imaging, in combination with conventional molecular biology approaches—to answer fundamental questions concerning enzyme function and regulation. His research program is underpinned by single-molecule instrumentation that his laboratory designs and builds to elucidate enzyme mechanisms at the molecular level.
Approximately two meters of DNA is compacted into a cell’s nucleus, which leads to topological complications during replication, transcription, and segregation of chromosomes. Topoisomerases are essential enzymes that regulate DNA topology and are important chemotherapeutic and antibiotic drug targets; Dr. Neuman focuses on elucidating the molecular mechanisms of topoisomerase activity and inhibition by chemotherapeutic agents.
Topoisomerases interact with many other enzymes that regulate DNA. Dr. Neuman is extending the use of single-molecule techniques to dissect multi-enzyme complex formation and activity. For this work, he focuses on the combination of RecQ helicase and topoisomerase III, which is a conserved interaction in organisms ranging from E. coli through humans and plays important roles in genome stability and chromosome segregation.
Moving beyond the cell nucleus, and beyond the cell, Dr. Neuman studies the interaction between the structural protein collagen and the matrix metalloproteinase enzymes (collagenase) that remodel collagen. By measuring the motion of individual collagenase enzymes as they move along and degrade individual native collagen fibrils he can probe aspects of fibrillar collagen and the cleavage process. This enzymatic degradation reaction is important in a host of human pathological and physiological process including the rupture of atherosclerotic plaques and cancer metastasis.
Keir Neuman graduated cum laude with a B.A. in physics and applied math from the University of California, Berkeley in 1994 and received his Ph.D. in physics from Princeton University in 2002. He did postdoctoral research with Steven Block at Stanford University from 2002 to 2004, and was a Human Frontiers Fellow with David Bensimon and Vincent Croquette at the Laboratoire de Physique Statistique at the École Normale Supérieure in Paris, France from 2004 to 2007. Dr. Neuman joined the NHLBI as a tenure-track Investigator in 2007 and was promoted to senior investigator in 2015. Dr. Neuman is a member of the Biophysical Society, the Optical Society of America, and the American Physical Society.
- Seol Y, Harami GM, Kovács M, Neuman KC. Homology sensing via non-linear amplification of sequence dependent pausing by RecQ helicase. Elife. 2019;8.
- Mills M, Tse-Dinh YC, Neuman KC. Direct observation of topoisomerase IA gate dynamics. Nat Struct Mol Biol. 2018;25(12):1111-1118.
- Jung HS, Cho KJ, Seol Y, Takagi Y, Dittmore A, Roche PA, Neuman KC. Polydopamine encapsulation of fluorescent nanodiamonds for biomedical applications. Adv Funct Mater. 2018;28(33).
- Seol Y, Neuman KC. Combined Magnetic Tweezers and Micro-mirror Total Internal Reflection Fluorescence Microscope for Single-Molecule Manipulation and Visualization. Methods Mol Biol. 2018;1665:297-316.
- Dittmore A, Brahmachari S, Takagi Y, Marko JF, Neuman KC. Supercoiling DNA Locates Mismatches. Phys Rev Lett. 2017;119(14):147801.
Related Scientific Focus Areas
Biomedical Engineering and Biophysics
Molecular Biology and Biochemistry
This page was last updated on Monday, September 9, 2019