Lab at posters.

Lab Research Interest

The Comstock lab investigates fundamental physical processes in biology using advanced, precision single-molecule measurement and manipulation techniques. We observe in real-time individual protein molecular machines marching down DNA strands or ripping open RNA. We manipulate live cells and measure individual cellular electrochemistry. To do this we design and build frontier biophysical instrumentation combining optical tweezers and single-molecule fluorescence microscopy. We strive to watch biology in action without the obscuring effects of traditional ensemble methods.

We are a young interdisciplinary lab composed of scientists with a diversity of backgrounds. Students have the opportunity to participate in all aspects of biophysical research including: wet lab development and production of biological systems, design and construction of instrumentation (optics, electronics, software etc.), quantitative data analysis and modeling and collegial discussion. We are always on the lookout for excited new colleagues. Interested students and postdocs with a background in physics, biology, chemistry, or a related field are welcome to contact Prof. Comstock.

News

April 8, 2019 We have funding for new postdoctoral and/or graduate students to work on our RNA processing protein nanomachine projects. Please inquire with Prof. Matt Comstock at mjcomsto@msu.edu. For a postdoctoral position, apply at the official MSU job posting site:

http://careers.msu.edu/cw/en-us/job/501547/research-associatefixed-term

Cho-Ying thesis defense photo.

January 3, 2019 Congratulations to new PhD, Dr. Cho-Ying Chuang, our trapping lab's second successful PhD thesis!

Cho-Ying was a major asset to the lab, helping to build the lab and develop new fluorescence and tweezers methods. Among other projects, she made very high resolution measurements of very small nucleic acids folding (stay tuned!).

Mtr4p unwinding RNA cartoon.

October, 2018 Together with the Lapidus lab, we have published a high-resolution force spectroscopy investigation of the folding and unfolding of a model protein, GB1. We performed equilibrium measurements down to very low forces and observed a clear transition from a high force mechanical unfolding mechanism to a low force more 'native-like' unfolding mechanism - a transition that has been seen only rarely previously. The high force results agree with previous out-of-equilibrium high pulling force results while the low force results seem to extrapolate much closer to ensemble results. This work highlights the potential for the coexistence of multiple folding and unfolding pathways and how they can mask each other in different force ranges. This reinforces the need to take care when extrapolating force spectroscopy data to zero force. We published our work in the recent 'Festschrift' honoring Bill Eaton:

"Combined force ramp and equilibrium high-resolution investigations reveal multi-path heterogeneous unfolding of protein G," Journal of Physical Chemistry B, 122, 11155 (2018).

AOD wiggle removal.

February, 2018 We have published a method to completely vanquish optical trap positioning and measurement errors, known as 'wiggles', arising from acousto optic devices! These errors have long plauged high resolution methods in particular. While some workarounds exist, we show how simply reducing the coherence of the RF drive signal can completely remove the wiggles. This enhances tweezers stability and accuracy particularly for long measurement durations. The new 'random phase' method can be implemented via a software change in the RF synthesis method - no new equipment is necessary. Our latest high-resolution fleezers instrument software which incorporates this upgrade is now available for download.

"Randomizing phase to remove acousto-optic device wiggle errors for high-resolution optical tweezers ," Applied Optics 57, 1752 (2018).

High time resolution tweezers analysis.

January, 2018 In collaboration with Steve Pressé's group at Arizona State, we have published a new method for accurately analyzing high-resolution optical tweezers data acquired at high time resolution. The method is an expansion of Steve's model-free Bayesian nonparametric methods of extracting states and rates from single molecule data in a statistically rigorous manner without having to pre-specify state identities. The method self-consistently accounts for signal drift (very important for high-resolution tweezers data) and now also explicitly incorporates the optical trap measurement response time, which is essential for correctly analyzing high time resolution data down to the microsecond timescale.

"Single molecule force spectroscopy at high data acquisition: A Bayesian nonparametric analysis," Journal of Chemical Physics 148, 123320 (2018).

Mtr4p unwinding RNA cartoon.

October 26, 2017 Congratulation to newly minted Dr. Dena Izadi, our trapping lab's first successful PhD thesis!

Dena investigated protein folding complexity at high resolution and was co-advised by Prof. Lisa Lapidus.

Mtr4p unwinding RNA cartoon.

November 21, 2016 Our work on the nuclear RNA helicase Mtr4p and TRAMP has been published in Nature Chemical Biology!

E. M. Patrick, Sukanya Srinivasan, Eckhard Jankowsky, and M. J. Comstock. “The RNA Helicase Mtr4p is a Duplex Sensing Translocase.” Nature Chemical Biology, 13, 99 (2017).

The work was led by our postdoc, Eric Patrick, in collaboration with Eckhard Jankowsky's lab at Case Western. We have directly shown that this helicase is a slow translocase that stalls without an upstream duplex to unwind.

NSF logo

September 1, 2015 Our technique has been featured again in Genetic Engineering and Biotechnology News (GEN): More Dynamic Protein Profiling. See on page 2: Single Molecule Nanometry.

June 28, 2015 We have received our first extramual funding! We have received a regular NSF award for "Investigation of RNA-Processing Protein Dynamics with Simultaneous High-Resolution Optical Traps and Single-Molecule Fluorescence" (MCB-1514706).

Fleezers measurement of helicase cartoon.

April 17, 2015 Matt's postdoctoral work (Chemla and Ha labs) is published in Science!

M.J. Comstock, K.D. Whitley, H. Jia, J. Sokoloski, T.M. Lohman, Taekjip Ha, and Y.R. Chemla. “Direct observation of structure-function relationship in a nucleic acid-processing enzyme,” Science, 348, 352 (2015).

Here we directly observe the dependence of helicase unwinding activity on protein stoichiometry and conformation.

Support

We are presently supported by the National Science Foundation (MCB-1514706), MSU startup funds and the Cowen Endowed Chair which was made possible by the generous support of Randy Cowen and his family.

 

Matt Comstock, Department of Physics and Astronomy, Michigan State University

Biomedical Physical Sciences, 567 Wilson Road, Room 4216