From The College of Arts and Sciences At Cornell University Via “The Chronicle”: “Picking up good vibrations – of proteins – at CHESS”
From The College of Arts and Sciences
At
Via
5.10.23
Rick Ryan | Cornell Laboratory for Accelerator-Based Sciences and Education
A new method for analyzing protein crystals – developed by Cornell researchers and given a funky two-part name – could open up applications for new drug discovery and other areas of biotechnology and biochemistry.
The development, outlined in a paper published March 3 in Nature Communications [below], provides researchers with the tools to interpret the once-discarded data from X-ray crystallography experiments – an essential method used to study the structures of proteins. This work, which builds on a study released in 2020 [Nature Communications (below)], could lead to a better understanding of a protein’s movement, structure and overall function.
As a structural biologist, Nozomi Ando, M.S. ’04, Ph.D. ’09, assistant professor of chemistry and chemical biology, is interested in charting the motion of proteins, and their internal parts, to better understand protein function. This type of movement is well known but has been difficult to document because the standard technique for imaging proteins is X-ray crystallography, which produces essentially static snapshots.
“Because we’re studying really challenging biological systems, the group often has to pioneer new structural methods as well,” said postdoctoral researcher Steve Meisburger, Ph.D. ’14, the paper’s lead author. “One of the questions that we have been interested in since the beginning is how a protein’s subtle breathing motions direct biochemical function.”
Protein crystallography produces bright spots, known as “Bragg peaks”, from the crystals, providing high-resolution information about the shape and structure of a protein. This process also captures blurry images – patterns and clouds related to the movement and vibrations of the proteins – hidden in the background of the Bragg peaks.
These background images are typically discarded, with priority given to the bright Bragg peak imagery that is more easily analyzed.
“We know that this pattern is related to the motion of the atoms of the protein, but we haven’t been able to use that information,” said lead author Steve Meisburger, Ph.D. ’14, a former postdoctoral researcher in the lab of Nozomi Ando, M.S. ’04, Ph.D. ’09, associate professor of chemistry and chemical biology in the College of Arts and Sciences. “The information is there, but we didn’t know how to use it. Now we do.”
Meisburger worked closely with Ando to develop the robust workflow to decode the weak background signals from crystallography experiments called diffuse scattering. This allows researchers to analyze the total scattering from crystals, which depends on both the protein’s structure and the subtle blur of its movements.
Their two-part method – which the team dubbed GOODVIBES and DISCOBALL – simultaneously provides a high-resolution structure of the protein and information on its correlated atomic movements.
“GOODVIBES” analyzes the X-ray data by separating the movements – subtle vibrations – of the protein from other proteins that might be moving around it. “DISCOBALL” independently validates these movements for certain proteins directly from the data, allowing researchers to trust the results from GOODVIBES and understand what the protein might be doing.
Ando said that while the potential for using diffuse scattering has been recognized for a long time, the act of accurately measuring the subtle signal while processing the data for something useful has been very difficult to do.
“It is much more computationally intensive to analyze than trying to analyze crystallography data alone,” Ando said. “We have a lot more data to deal with in diffuse scattering, because we are looking everywhere all at once, and the signal is also very nuanced.“
The overarching goal, Ando said, is to turn GOODVIBES and DISCOBALL into a genuine structural technique that can be used by researchers at synchrotrons all over the world.
“There is a lot of interest within the structural biology and biochemistry fields to use this signal,” Ando said. “We weren’t satisfied with just understanding what’s contained in the signal; it was really important for us to make the next step of creating the tools, and making GOODVIBES and DISCOBALL available for others to use these tools and test their hypotheses.”
These methods were developed using lysozyme proteins collected at the Cornell High Energy Synchrotron Source (CHESS).
The Ando group will be returning to CHESS this spring to collaborate with Meisburger, now a CHESS staff scientist, on more complex protein structures using their new method.
By isolating the internal motion signals from total scattering data of these complex proteins, researchers can learn more about how proteins move and interact with other important molecules. This information can be used to design new drugs and therapies that target specific proteins.
Experiments were performed at the Center for High Energy X-ray Sciences (CHEXS), which is supported by the National Science Foundation, and the Macromolecular Diffraction at CHESS (MacCHESS) facility, which is supported by the National Institute of General Medical Sciences, the National Institutes of Health (NIH) and New York State’s Empire State Development Corporation. This work was supported by grants from the NIH.
Fig. 1: Workflow to measure and interpret protein correlated motion using X-ray crystallography.
First, X-ray diffraction images are acquired from protein crystals at room temperature (RT-MX). The Bragg peaks and continuous scattering are processed separately to obtain the protein structure and a three-dimensional map of diffuse scattering on an absolute intensity scale (electron units). The structure includes mean atomic positions and atomic displacement parameters (ADPs or B-factors) that quantify motion, and the pattern of diffuse scattering depends on how motions are correlated. To separate the internal and external (rigid-body) protein motions, a physical model of lattice disorder is refined to the intense diffuse halo features (GOODVIBES), and the lattice contribution to the diffuse map and variance-covariance matrix of rigid-body motion (V-Cov) are simulated. In parallel, a model-free analysis is performed to estimate displacement covariances (DISCOBALL) and validate the off-diagonal elements of the simulated lattice V-Cov (yellow shading). The lattice contribution to the diffuse map is subtracted and the residual diffuse scattering is sorted by inter-atomic vector using a Fourier transform (3D-ΔPDF). Similarly, the internal ADPs are found by subtracting the lattice contribution (diagonal blocks of V-Cov, blue shading). The internal motion signal can be interpreted by various models. To match crystal simulations, a target diffuse map can be created using GOODVIBES to add back external motions that are consistent with the specific supercell used by the simulations.
Fig. 1: Diffuse scattering map of triclinic lysozyme with intensities on an absolute scale of electron units (Ie).
a) Ribbon diagram of lysozyme (top) and the triclinic unit cell containing one protein (bottom). b) A highly detailed three-dimensional map of diffuse scattering was obtained. The outer sphere is drawn at 2 Å resolution. c) The total scattering is made up of three components: inelastic Compton scattering (lower left), a broad isotropic ring that dominates the diffuse signal (upper left), and variational features in the diffuse scattering (right). Intense halos are visible in the layers containing Bragg peaks (l = 0 plane, upper right). Cloudy scattering is best visualized in the planes mid-way between the Bragg peaks (l = 1∕2 plane, lower right).
See the full article here .
Comments are invited and will be appreciated, especially if the reader finds any errors which I can correct. Use “Reply”.
five-ways-keep-your-child-safe-school-shootings
Please help promote STEM in your local schools.
The College of Arts and Sciences is a division of Cornell University. It has been part of the university since its founding, although its name has changed over time. It grants bachelor’s degrees, and masters and doctorates through affiliation with the Cornell University Graduate School. Its major academic buildings are located on the Arts Quad and include some of the university’s oldest buildings. The college offers courses in many fields of study and is the largest college at Cornell by undergraduate enrollment.
Originally, the university’s faculty was undifferentiated, but with the founding of the Cornell Law School in 1886 and the concomitant self-segregation of the school’s lawyers, different departments and colleges formed.
Initially, the division that would become the College of Arts and Sciences was known as the Academic Department, but it was formally renamed in 1903. The College endowed the first professorships in American history, musicology, and American literature. Currently, the college teaches 4,100 undergraduates, with 600 full-time faculty members (and an unspecified number of lecturers) teaching 2,200 courses.
The Arts Quad is the site of Cornell’s original academic buildings and is home to many of the college’s programs. On the western side of the quad, at the top of Libe Slope, are Morrill Hall (completed in 1866), McGraw Hall (1872) and White Hall (1868). These simple but elegant buildings, built with native Cayuga bluestone, reflect Ezra Cornell’s utilitarianism and are known as Stone Row. The statue of Ezra Cornell, dating back to 1919, stands between Morrill and McGraw Halls. Across from this statue, in front of Goldwin Smith Hall, sits the statue of Andrew Dickson White, Cornell’s other co-founder and its first president.
Lincoln Hall (1888) also stands on the eastern face of the quad next to Goldwin Smith Hall. On the northern face are the domed Sibley Hall and Tjaden Hall (1883). Just off of the quad on the Slope, next to Tjaden, stands the Herbert F. Johnson Museum of Art, designed by I. M. Pei. Stimson Hall (1902), Olin Library (1959) and Uris Library (1892), with Cornell’s landmark clocktower, McGraw Tower, stand on the southern end of the quad.
Olin Library replaced Boardman Hall (1892), the original location of the Cornell Law School. In 1992, an underground addition was made to the quad with Kroch Library, an extension of Olin Library that houses several special collections of the Cornell University Library, including the Division of Rare and Manuscript Collections.
Klarman Hall, the first new humanities building at Cornell in over 100 years, opened in 2016. Klarman houses the offices of Comparative Literature and Romance Studies. The building is connected to, and surrounded on three sides by, Goldwin Smith Hall and fronts East Avenue.
Legends and lore about the Arts Quad and its statues can be found at Cornelliana.
The College of Arts and Sciences offers both undergraduate and graduate (through the Graduate School) degrees. The only undergraduate degree is the Bachelor of Arts. However, students may enroll in the dual-degree program, which allows them to pursue programs of study in two colleges and receive two different degrees. The faculties within the college are:
Africana Studies and Research Center*
American Studies
Anthropology
Archaeology
Asian-American Studies
Asian Studies
Astronomy/Astrophysics
Biology (with the College of Agriculture and Life Sciences)
Biology & Society Major (with the Colleges of Agriculture and Life Sciences and Human Ecology)
Chemistry and Chemical Biology
China and Asia-pacific Studies
Classics
Cognitive Studies
College Scholar Program (frees up to 40 selected students in each class from all degree requirements and allows them to fashion a plan of study conducive to achieving their ultimate intellectual goals; a senior thesis is required)
Comparative Literature
Computer Science (with the College of Engineering)
Earth and Atmospheric Sciences (with the Colleges of Agriculture and Life Sciences and Engineering)
Economics
English
Feminist, Gender, and Sexuality Studies
German Studies
Government
History
History of Art
Human Biology
Independent Major
Information Science (with the College of Agriculture and Life Sciences and College of Engineering)
Jewish Studies
John S. Knight Institute for Writing in the Disciplines
Latin American Studies
Latino Studies
Lesbian, Gay, Bisexual, and Transgender Studies
Linguistics
Mathematics
Medieval Studies
Modern European Studies Concentration
Music
Near Eastern Studies
Philosophy
Physics
Psychology
Religious Studies
Romance Studies
Russian
Science and Technology Studies
Society for the Humanities
Sociology
Theatre, Film, and Dance
Visual Studies Undergraduate Concentration
*Africana Studies was an independent center reporting directly to the Provost until July 1, 2011.
Once called “the first American university” by educational historian Frederick Rudolph, Cornell University represents a distinctive mix of eminent scholarship and democratic ideals. Adding practical subjects to the classics and admitting qualified students regardless of nationality, race, social circumstance, gender, or religion was quite a departure when Cornell was founded in 1865.
Today’s Cornell reflects this heritage of egalitarian excellence. It is home to the nation’s first colleges devoted to hotel administration, industrial and labor relations, and veterinary medicine. Both a private university and the land-grant institution of New York State, Cornell University is the most educationally diverse member of the Ivy League.
On the Ithaca campus alone nearly 20,000 students representing every state and 120 countries choose from among 4,000 courses in 11 undergraduate, graduate, and professional schools. Many undergraduates participate in a wide range of interdisciplinary programs, play meaningful roles in original research, and study in Cornell programs in Washington, New York City, and the world over.
Cornell University is a private, statutory, Ivy League and land-grant research university in Ithaca, New York. Founded in 1865 by Ezra Cornell and Andrew Dickson White, the university was intended to teach and make contributions in all fields of knowledge—from the classics to the sciences, and from the theoretical to the applied. These ideals, unconventional for the time, are captured in Cornell’s founding principle, a popular 1868 quotation from founder Ezra Cornell: “I would found an institution where any person can find instruction in any study.”
The university is broadly organized into seven undergraduate colleges and seven graduate divisions at its main Ithaca campus, with each college and division defining its specific admission standards and academic programs in near autonomy. The university also administers two satellite medical campuses, one in New York City and one in Education City, Qatar, and The Jacobs Technion-Cornell Institute in New York City, a graduate program that incorporates technology, business, and creative thinking. The program moved from Google’s Chelsea Building in New York City to its permanent campus on Roosevelt Island in September 2017.
Cornell is one of the few private land-grant universities in the United States. Of its seven undergraduate colleges, three are state-supported statutory or contract colleges through The State University of New York (SUNY) system, including its Agricultural and Human Ecology colleges as well as its Industrial Labor Relations school. Of Cornell’s graduate schools, only the veterinary college is state-supported. As a land grant college, Cornell operates a cooperative extension outreach program in every county of New York and receives annual funding from the State of New York for certain educational missions. The Cornell University Ithaca Campus comprises 745 acres, but is much larger when the Cornell Botanic Gardens (more than 4,300 acres) and the numerous university-owned lands in New York City are considered.
Alumni and affiliates of Cornell have reached many notable and influential positions in politics, media, and science. As of January 2021, 61 Nobel laureates, four Turing Award winners and one Fields Medalist have been affiliated with Cornell. Cornell counts more than 250,000 living alumni, and its former and present faculty and alumni include 34 Marshall Scholars, 33 Rhodes Scholars, 29 Truman Scholars, 7 Gates Scholars, 55 Olympic Medalists, 10 current Fortune 500 CEOs, and 35 billionaire alumni. Since its founding, Cornell has been a co-educational, non-sectarian institution where admission has not been restricted by religion or race. The student body consists of more than 15,000 undergraduate and 9,000 graduate students from all 50 American states and 119 countries.
History
Cornell University was founded on April 27, 1865; the New York State (NYS) Senate authorized the university as the state’s land grant institution. Senator Ezra Cornell offered his farm in Ithaca, New York, as a site and $500,000 of his personal fortune as an initial endowment. Fellow senator and educator Andrew Dickson White agreed to be the first president. During the next three years, White oversaw the construction of the first two buildings and traveled to attract students and faculty. The university was inaugurated on October 7, 1868, and 412 men were enrolled the next day.
Cornell developed as a technologically innovative institution, applying its research to its own campus and to outreach efforts. For example, in 1883 it was one of the first university campuses to use electricity from a water-powered dynamo to light the grounds. Since 1894, Cornell has included colleges that are state funded and fulfill statutory requirements; it has also administered research and extension activities that have been jointly funded by state and federal matching programs.
Cornell has had active alumni since its earliest classes. It was one of the first universities to include alumni-elected representatives on its Board of Trustees. Cornell was also among the Ivies that had heightened student activism during the 1960s related to cultural issues; civil rights; and opposition to the Vietnam War, with protests and occupations resulting in the resignation of Cornell’s president and the restructuring of university governance. Today the university has more than 4,000 courses. Cornell is also known for the Residential Club Fire of 1967, a fire in the Residential Club building that killed eight students and one professor.
Since 2000, Cornell has been expanding its international programs. In 2004, the university opened the Weill Cornell Medical College in Qatar. It has partnerships with institutions in India, Singapore, and the People’s Republic of China. Former president Jeffrey S. Lehman described the university, with its high international profile, a “transnational university”. On March 9, 2004, Cornell and Stanford University laid the cornerstone for a new ‘Bridging the Rift Center’ to be built and jointly operated for education on the Israel–Jordan border.
Research
Cornell, a research university, is ranked fourth in the world in producing the largest number of graduates who go on to pursue PhDs in engineering or the natural sciences at American institutions, and fifth in the world in producing graduates who pursue PhDs at American institutions in any field. Research is a central element of the university’s mission; in 2009 Cornell spent $671 million on science and engineering research and development, the 16th highest in the United States.
Cornell is a member of the Association of American Universities and is classified among “R1: Doctoral Universities – Very high research activity”.
For the 2016–17 fiscal year, the university spent $984.5 million on research. Federal sources constitute the largest source of research funding, with total federal investment of $438.2 million. The agencies contributing the largest share of that investment are The Department of Health and Human Services and the National Science Foundation, accounting for 49.6% and 24.4% of all federal investment, respectively. Cornell was on the top-ten list of U.S. universities receiving the most patents in 2003, and was one of the nation’s top five institutions in forming start-up companies. In 2004–05, Cornell received 200 invention disclosures; filed 203 U.S. patent applications; completed 77 commercial license agreements; and distributed royalties of more than $4.1 million to Cornell units and inventors.
Since 1962, Cornell has been involved in unmanned missions to Mars. In the 21st century, Cornell had a hand in the Mars Exploration Rover Mission. Cornell’s Steve Squyres, Principal Investigator for the Athena Science Payload, led the selection of the landing zones and requested data collection features for the Spirit and Opportunity rovers. NASA-JPL/Caltech engineers took those requests and designed the rovers to meet them. The rovers, both of which have operated long past their original life expectancies, are responsible for the discoveries that were awarded 2004 Breakthrough of the Year honors by Science. Control of the Mars rovers has shifted between National Aeronautics and Space Administration ’s Jet Propulsion Laboratory at The California Institute of Technology and Cornell’s Space Sciences Building.
Further, Cornell researchers discovered the rings around the planet Uranus, and Cornell built and operated the telescope at Arecibo Observatory located in Arecibo, Puerto Rico until 2011, when they transferred the operations to SRI International, the Universities Space Research Association and the Metropolitan University of Puerto Rico [Universidad Metropolitana de Puerto Rico].
The Automotive Crash Injury Research Project was begun in 1952. It pioneered the use of crash testing, originally using corpses rather than dummies. The project discovered that improved door locks; energy-absorbing steering wheels; padded dashboards; and seat belts could prevent an extraordinary percentage of injuries.
In the early 1980s, Cornell deployed the first IBM 3090-400VF and coupled two IBM 3090-600E systems to investigate coarse-grained parallel computing. In 1984, the National Science Foundation began work on establishing five new supercomputer centers, including the Cornell Center for Advanced Computing, to provide high-speed computing resources for research within the United States. As a National Science Foundation center, Cornell deployed the first IBM Scalable Parallel supercomputer.
In the 1990s, Cornell developed scheduling software and deployed the first supercomputer built by Dell. Most recently, Cornell deployed Red Cloud, one of the first cloud computing services designed specifically for research. Today, the center is a partner on the National Science Foundation XSEDE-Extreme Science Engineering Discovery Environment supercomputing program, providing coordination for XSEDE architecture and design, systems reliability testing, and online training using the Cornell Virtual Workshop learning platform.
Cornell scientists have researched the fundamental particles of nature for more than 70 years. Cornell physicists, such as Hans Bethe, contributed not only to the foundations of nuclear physics but also participated in the Manhattan Project. In the 1930s, Cornell built the second cyclotron in the United States. In the 1950s, Cornell physicists became the first to study synchrotron radiation.
During the 1990s, the Cornell Electron Storage Ring, located beneath Alumni Field, was the world’s highest-luminosity electron-positron collider. After building the synchrotron at Cornell, Robert R. Wilson took a leave of absence to become the founding director of The DOE’s Fermi National Accelerator Laboratory, which involved designing and building the largest accelerator in the United States.
Cornell’s accelerator and high-energy physics groups are involved in the design of the proposed ILC-International Linear Collider(JP) and plan to participate in its construction and operation. The International Linear Collider(JP), to be completed in the late 2010s, will complement the CERN Large Hadron Collider(CH) and shed light on questions such as the identity of dark matter and the existence of extra dimensions.
As part of its research work, Cornell has established several research collaborations with universities around the globe. For example, a partnership with the University of Sussex(UK) (including the Institute of Development Studies at Sussex) allows research and teaching collaboration between the two institutions.
Reply