Williams Lab News
February 2020 - Professor Williams featured as part of the LUMICKS Dynamic Single-Molecule Symposium Series
The single molecule research from the Williams Lab was features as a keynote video presentation in the 8-part Lumicks Dynamic Single-Molecule Symposium Series. See the entire series here: https://t.co/r8gJJe0YV4?amp=1. Watch the Williams Lab video here:
August 2019 - The 11th International Retroviral Nucleocapsid and Assembly Symposium
Northeastern hosted the 11th International Retroviral Nucleocapsid and Assembly Symposium, August 15-17, 2019. The symposium provided a venue for ~80 researchers (principal investigators, postdoctoral fellows, students, research staff and representatives from biotechnology) to make progress in efforts to combat HIV-1/AIDS, as well as other retroviral diseases.
January 2019 - Unraveling the mysteries hidden in DNA
Principal Research Scientist Micah McCauley and graduate student Ran Huo published a paper in Nucleic Acids Research describing how HMGB proteins faciliate access to packaged DNA. See full Northeastern College of Science story here.
October 2018 - $1.1 M NSF Major Research Instrument grant received
Professor Williams and colleagues have received a $1.1 M NSF MRI grant to purchase a Lumicks SuperC-TRAP correlative optical tweezers and fluorescence microscope system. The CTFM instrument will allow users to measure and apply tension to single biomolecules with sub-picoNewton resolution, and to detect the presence, number, and position of individual fluorescently labeled molecules during these measurements in real time. This allows users to push or pull on biological systems and observe the reaction of the systems to force by using fluorescent labels. Simultaneously, the users can "feel" the reaction of the systems to these inputs through measurements of force or extension changes as the system responds to these inputs. Importantly, these observations reveal interactions at very small length scales, revealing activities of single proteins interacting with a substrate. Innovative projects at the forefront of interdisciplinary science will be enabled by this instrument, including projects to study how cellular DNA replication and repair of DNA damage occurs, how retroviruses copy their genomes, and how DNA is packaged (and can be unpackaged) in cells. Studies on collagen will probe how force affects tissue repair, while studies on polymer dynamics will use force to observe and direct protein assembly. The results of these studies will allow observation of real-time biological dynamics at the single molecule level, providing significant new insights into the functions of the biological systems probed.
August 2018 - NSF: Quantifying Single Molecule DNA-ligand Interactions
The Williams Lab has received a $900K grant from the National Science Foundation to continue studies of single molecule DNA interactions. This project uses DNA stretching with optical tweezers to probe biologically important molecular-level nucleic acid interactions that are particularly well-suited to probe with single molecule methods. Small molecule-DNA interactions will be studied, particularly for cases in which significant DNA structural rearrangements are required for DNA binding and dissociation. The properties of these small molecules that determine the DNA unfolding landscape will be measured, revealing critical information needed for the design of useful new ligands. LINE1 is a retrotransposon that is active in human cells. Recent studies probed the interaction between an essential LINE1-encoded protein, ORF1p, with nucleic acid, showing that its universally conserved coiled coil motif facilitates ORF1p oligomerization on nucleic acid. This project will probe the biophysical mechanism responsible for oligomerization, a process that is essential for retrotransposition. Finally, the activity of several E. coli DNA polymerases and polymerase manager or accessory proteins will be studied. These studies will reveal detailed interactions that are part of the bacterial response to DNA damage, a response essential for all life. This project is jointly funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Division of Physics.
October 2017 - One if by editing, two if by roadblock: Human protein fights HIV as monomer and dimer
Williams Lab postdoc Mike Morse and graduate student Ran Huo published a paper in Nature Communications describing APOBEC3G, a human innate immunity protein that is a cellular weapon in the battle with HIV-1 and retrotransposons.
See full Northeastern College of Science story here and the press release here.
December 2016 - Interview with Professor Williams in NEU College of Science Newsletter
Faculty Feature
Dr. Mark Williams
Professor, Department of Physics
We sat down with Dr. Mark Williams, Professor in the Department of Physics, and learned about how molecules, such as DNA, work and interact. See part of the interview below, and read the full interview here.
June 2015 - Williams lab awarded $1.5M NIH grant to continue studies on HIV-1 replication interactions
The objective of the funded work is to investigate the role of the HIV-1 nucleocapsid (NC) and reverse transcriptase (RT) proteins, as well as human APOBEC3 viral restriction factors, in the regulation of reverse transcription in retroviral systems. The proposed work combines single molecule methods with biochemical methods and measurements in cells to obtain a complete understanding of nucleic acid interactions involved in retroviral replication. We use these methods to probe the mechanisms by which retroviral proteins dynamically restructure and organize nucleic acids to facilitate replication, and to determine how these processes are regulated. To do this, the Williams Lab has pioneered single molecule nucleic acid stretching methods that quantitatively probe nucleic acid structural rearrangements and protein-nucleic acid interactions. In the previous cycle, we demonstrated that the capability of NCs to rearrange nucleic acids, referred to as nucleic acid chaperone activity, is directly correlated with HIV-1 replication in cells. The proposed work seeks to understand how this chaperone activity targets specific structures and facilitates nucleic acid reorganization without interfering with reverse transcription. In contrast to NC’s facilitation of reverse transcription, human APOBEC3 proteins may inhibit reverse transcriptase activity. We plan to probe the DNA interactions of several APOBEC3 proteins and directly monitor RT activity in the presence of APOBEC3 proteins as well as NC. The award amount is over $1.5M total for four additional years of research.
November 2013 - Bonding Together to Fight HIV: Nature Chemistry Manuscript Describes New Mechanism for Inhibition of HIV by APOBEC3G
Bonding Together to Fight HIV
A collaborative team led by a Northeastern University professor may have altered the way we look at drug development for HIV by uncovering some unusual properties of a human protein called APOBEC3G (A3G).
In an article published in Nature Chemistry, Prof. Mark Williams and his graduate student Kathy Chaurasiya, along with several collaborators, show how these unusual properties help us to fight HIV infection.
APOBEC3G
It is well known that in response to virus infection, the body makes specific antibodies to counteract the infection. However, we are also born with another way to fight infection, namely through the action of defense proteins that are always present in our system. These proteins provide the first line of defense against invading pathogens. For example, we are all potentially protected against HIV because we have an antiviral protein called A3G. However, HIV has evolved a strategy to circumvent the activity of this protein by tricking our cells into destroying our own A3G proteins. This is where Prof. Williams’s research comes into play.
A MULTI-FUNCTIONAL PROTEIN
A3G moves along a DNA strand as part of its function as an enzyme and when it reaches a particular one of the four bases in DNA, it chemically alters the DNA, causing HIV to mutate. This was originally thought to be the only way A3G blocks HIV infection. However, some researchers found that even when A3G could not chemically alter the DNA, it still inhibited HIV. To explain this, Prof. Williams’s collaborator Dr. Judith Levin from NIH, together with former postdoctoral fellow Dr. Yasumasa Iwatani proposed that A3G forms a roadblock that prevents the virus from making a DNA copy of its genome, thereby stopping HIV replication. This would require A3G to be more slow-acting, yet because the protein normally has to move fast to perform its chemical function, there seemed to be an apparent contradiction in the experimental results.
Professor Williams’s research resolves this paradox and shows that the A3G protein does not always have the rapid movement needed for chemical function. Instead, its activity changes over time. “First, A3G is a really fast protein,” said Williams. “Then, gradually over time, it becomes a slow protein and remains bound to the DNA, blocking replication.”
CHALLENGING POPULAR OPINION
Many researchers doubted that a protein could have both enzyme and roadblock functions. An enzyme is designed to act rapidly, so the idea of the A3G protein starting off fast, and then gradually slowing down seemed physically impossible. Professor Williams’s collaborator Dr. Ioulia Rouzina from the University of Minnesota came up with the novel idea that when A3G proteins group together, they become slower over time. To test the idea, the Williams lab used an instrument called optical tweezers that allowed them to stretch single DNA molecules with A3G proteins bound. By measuring the change in DNA length over time as the proteins came on and off the DNA, they could show that the rates at which A3G bound to DNA became slower over time.
How does this happen? It was already known that A3G proteins bind to each other and form a multi-protein complex. “Once the complex is formed, the A3G proteins are no longer able to move rapidly along the DNA strand as needed for chemical modification of the DNA. This suggests that slow binding can also block HIV replication.”
IMPACT ON HIV RESEARCH
The A3G protein has at least two mechanisms by which it can block HIV replication. We have known for over ten years that A3G can, in principle, provide protection from HIV. However, finding a drug that can counter the anti-A3G activity of the virus has been elusive. This new work has the potential to develop alternative approaches to HIV therapy and development of drugs that can enhance the roadblock activity of A3G. This provides an alternate pathway for drug development that has not previously been pursued.
In addition to members of Professor Williams’s laboratory at Northeastern University, other researchers contributing to this work included members of the laboratories of Professor Karin Musier-Forsyth at The Ohio State University, Dr. Judith Levin at the NIH, and Dr. Yasumasa Iwatani at Nagoya Medical Center. This research was generously supported by funding from the National Science Foundation and from the extramural and intramural programs at the NIH.
Note: This news item was released on November 25, 2013, and was picked up by several news sites: Science Codex, Phys.org, e! Science News, Science Daily, and many others. See also the Northeastern University News Story and the News and Views article by King and Wuite.
November 2012 - Professor Mark Williams Elected 2012 Fellow of the American Physical Society
Professor Mark Williams has been elected a Fellow of the American Physical Society this year. He was honored for "his original contributions to the development of the single molecule biophysics. In particular, for his use of quantitative models to describe the interactions of single DNA molecules with biologically important proteins and DNA binding ligands." The criterion for election is that the candidate has made exceptional contributions to physics, and the total number of fellows is limited to no more than one half of one percent of the APS membership.
October 2012 - Williams lab awarded $950,000 NSF grant to probe single molecule DNA-ligand interactions
The goal of this new project is to develop single molecule methods for the quantitative study of DNA interactions with small molecules and proteins and to use these methods to investigate specific biologically important systems. The PI Mark Williams and co-PI Megan Nunez from Mount Holyoke College will use several DNA constructs and data analysis methods to probe the thermodynamics and kinetics of DNA-ligand interactions and determine the time-dependent changes of DNA structure as proteins and small molecules bind. In addition to method development, this work will shed light on the fundamental biophysics of DNA-small molecule interactions as well as the biophysical and biochemical mechanisms of multiple protein interactions involved in retrotransposon replication and DNA damage response. The three specific aims of this project include probing the structural dynamics of DNA-small molecule interactions using single molecule force spectroscopy, studying dynamic protein-DNA interactions important for LINE1 retrotransposition, and investigating the protein-protein and protein-DNA binding interactions that participate in the management of DNA polymerase switching in E. coli. The total grant amount is $950,000 over 5 years, beginning March 1, 2013.
February 2012 - Latest paper in Nucleic Acids Research on the anti-cancer drug Actinomycin D featured in Northeastern News
In a recent manuscript published in Nucleic Acids Research, the Williams lab has developed a new method for characterizing the dynamics of DNA structure upon binding of a drug. Former graduate student Thayaparan Paramanathan (now a postdoc at Brandeis with Jeff Gelles) played the lead role in the project, in which the structural dynamics of DNA upon binding of the potent anti-cancer drug Actinomycin D were probed. These methods were developed along with models to describe the DNA dynamics by the Williams lab in collaboration with biophysical theorist Ioulia Rouzina from the University of Minnesota. The results show for the first time the DNA binding characteristics responsible for Actinomycin D's slow kinetics, which in turn are responsible for its anti-cancer activity.
Northeastern News Story: Laser show — for a cure, by Angela Herring
Manuscript link: Thayaparan Paramanathan, Ioana Vladescu, Micah J. McCauley, Ioulia Rouzina, and Mark C. Williams. Force spectroscopy reveals the DNA structural dynamics that govern the slow binding of Actinomycin D. Nucleic Acids Research (in press, 2012).
July 2011 - Williams appointed member of the NIH MSFC Study Section
Mark C. Williams has been appointed a regular member of the Macromolecular Structure and Function C Study Section in the NIH Center for Scientific Review, for the term beginning July 01, 2011 and ending June 30, 2017. According to a letter from the Center for Scientific Review, members are selected on the basis of their demonstrated competence and achievement in their scientific discipline as evidenced by the quality of research accomplishments, publications in scientific journals, and other significant scientific activities, achievements and honors. Membership on a study section represents a major commitment of professional time and energy as well as a unique opportunity to contribute to the national biomedical research effort. Study sections review grant applications submitted to the NIH, make recommendations on these applications to the appropriate NIH national advisory council or board, and survey the status of research in their fields of science. These functions are of great value to medical and allied research in this country.
January 2011 - Williams appointed to Nucleic Acids Research editorial board
Mark C. Williams has been appointed a member of the editorial board of Nucleic Acids Research. Nucleic Acids Research is an open access journal published by Oxford University Press. It is a top journal for work on nucleic acids, with a 2010 impact factor of 7.836, 30th out of 286 journals in the category Biochemistry and Molecular Biology.
January 2011 - DNA stretching in the news
A recent paper on DNA overstretching from the laboratory of Tom Perkins (J. Am. Chem. Soc., DOI: 10.1021/ja108952v) has generated several stories in the popular scientific press. Work from the Williams lab is referenced in the paper, and Mark Williams is quoted in several articles about the paper, including articles in Chemical and Engineering News, New Scientist, and Science News.
From the Back Cover: This book presents a concise overview of current research on the biophysics of DNA-protein interactions. A wide range of new and classical methods are presented by authors investigating physical mechanisms by which proteins interact with DNA. For example, several chapters address the mechanisms by which proteins search for and recognize specific binding sites on DNA, a process critical for cellular function. Single molecule methods such as force spectroscopy as well as fluorescence imaging and tracking are described in these chapters as well as other parts of the book that address the dynamics of protein-DNA interactions. Other important topics include the mechanisms by which proteins engage DNA sequences and/or alter DNA structure. These simple but important model interactions are then placed in the broader biological context with discussion of larger protein-DNA complexes . Topics include replication forks, recombination complexes, DNA repair interactions, and ultimately, methods to understand the chromatin context of the cell nucleus. This book will be of interest to readers who wish to explore current biophysical approaches to DNA-protein interactions across multiple levels of biological complexity.
May 2010 - Williams lab receives $1.2M NIH grant to continue studies on HIV-1 replication proteins
The Williams lab has received a 4 year, $1.2 million, continuation of its NIH grant to study HIV-1 replication. The grant, entitled "Single Molecule HIV-1 NC/Gag-DNA Interactions", is to develop and use novel single molecule biophysical methods to understand the mechanism by which specific proteins facilitate replication in HIV-1 and other retroviruses. For example, the HIV-1 nucleocapsid protein is essential for several steps in retroviral replication, and mutations in the protein prevent the virus from replicating. NC is therefore an excellent drug target. However, because the mechanism by which NC facilitates replication is not understood, there are no successful drugs that target this protein. Work on this system in the Williams lab seeks to develop a detailed biophysical understanding of NC's interaction with nucleic acids that allow it to facilitate replication in order to allow for rational drug design to target NC. To understand these interactions, optical tweezers are used to probe the interactions of wild type and mutant HIV-1 NC with single DNA and RNA molecules. This allows them to measure how specific residues on the protein contribute to its function. By comparing results with those of collaborators doing biochemical experiments on the same systems, as well as in vivo studies on HIV-1 replication with the same mutants, these studies will allow the development of detailed models for how HIV-1 NC functions. These models can then be used to help facilitate the design of drugs that target HIV-1 NC.
April 2010 - Graduate student Kathy Chaurasiya wins best poster contest at 2010 Inter-IGERT Nanoscience and Professional Development Workshop
Kathy Chaurasiya, graduate student in the Williams Laboratory, was selected to attend the 2010 Inter-IGERT Nanoscience and Professional Development Workshop hosted by the Trainees of the UT Austin IGERT (in Atomic and Molecular Imaging). The workshop was designed for Integrative Graduate Education and Research Traineeship (IGERT) students to share research experiences and avenues toward interdisciplinary work in nanoscience, and learn about aspects of professional life beyond graduate school from experts in their fields. The workshop coincided with the annual Nano Night poster session event hosted by UT-Austin's Center for Nano and Molecular Science and Technology. Kathy Chaurasiya was selected give an oral presentation, titled "Investigating quantum dot toxicity by quantifying DNA polymerase activity with optical tweezers". Her poster on the same topic was also selected as the best poster at the meeting.
October 2008 - Fast Breaking Paper Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G
Our recent collaborative paper with the laboratory of Judith G. Levin at NIH, entitled "Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G" as published in the journal NUCLEIC ACIDS RESEARCH in December 2007 has been identified by Thomson Reuters' Essential Science Indicators as a Fast Breaking Paper in the field of Biology & Biochemistry, which means it is one of the most-cited papers in its discipline published during the past two years (top 1%). The article is featured in the October 2008 issue of ScienceWatch.com. Northeastern University Physics Department graduate student Fei Wang from the laboratory of Mark C. Williams provided a key experiment for this work, showing that APOBEC3G exhibitied much slower nucleic acid binding kinetics than HIV-1 NC, and explaining why APOBEC3G did not interfere significantly with NC's nucleic acid chaperone activity.
July 2008 - Northeastern University Researchers Discover New DNA Binding Activity of E. coli Protein
Northeastern University scientists have discovered a new and unique DNA binding property of a protein in E. coli. Penny J. Beuning, Assistant Professor in the Department of Chemistry and Chemical Biology, spent the last two years researching double and single-stranded DNA binding of E. coli DNA polymerase III alpha protein and notes that her findings have potential for developing a new antibacterial target. Beuning's results have recently been published in ACS Chemical Biology in an article titled "Distinct Double- and Single-Stranded DNA Binding of E. coli Replicative DNA Polymerase III Alpha Subunit".
This work represents the collaborative effort of the Northeastern laboratories of Beuning and Mark C. Williams, Associate Professor of Physics, and involved researchers Micah J. McCauley, Leila Shokri, and Jana Sefcikova from both laboratories. Additionally, Česlovas Venclovas, of the Institute of Biotechnology in Lithuania, provided computational modeling expertise to the project. The project took advantage of the single-molecule expertise in the Williams laboratory and used a series of optical tweezers experiments to find that the DNA polymerase subunit of the 10-subunit bacterial replicative DNA enzyme has affinity for both double and single-stranded DNA in distinct subdomains of the protein. For more information, see the NEU press release. This work was also discussed in a journal podcast interview, and was featured on the following news sites: Newswise, PhysOrg.com
May 2008 - NU Physicists Demonstrate Precise Manipulation of DNA-Drug Interactions
Professor Mark Williams and his research team have developed a method of using optical tweezers to better understand how DNA-drug interactions occur. This research, performed primarily by graduate student Thaya Paramanathan, was recently published in the Journal of the American Chemical Society (vol. 130, p. 3752), has the potential to uncover crucial information about DNA binding in order to develop therapies for chronic diseases such as cancer and AIDS. For more information on this article, visit the NEU press release. This work was featured on the following news sites: Science Daily, Medical News Today