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In the late 17th century, Dutch businessman Anthoni van Leeuwenhoek (Anthoni van Leeuwenhoek) began to use the first microscope to study the extremely small world and discovered a riot of protists, bacteria and other unprecedented creatures.
Now, researchers from the Center for Applied Structure Discovery in Biological Design (CASD) and Arizona State University’s School of Molecular Sciences (SMS), as part of a multi-institutional research collaboration, have taken the field of microscopy one step forward and improved a method called cryo-electron microscopy.
This technology involves the rapid freezing of biological samples of interest, and then using electron beam imaging and recording thousands of two-dimensional images, which are then assembled into the atomic outline of the sample structure by a computer
This method is particularly useful for finding out the subtleties of protein structure, which are often overlooked in traditional modeling strategies
This new research describes a way to produce more precise structures through a complex statistical method called maximum entropy
Molecules like proteins have complex three-dimensional shapes and can also change shape during their function
The described new technology allows researchers to simulate these transient structures, which play a vital role in biological processes, but they are often ignored by traditional cryo-electromagnetic techniques
Researchers from the University of Illinois joined the research team at Arizona State University; Purdue University; the Department of Mathematics and Computer Science in Grenoble, France; the University of Florida; and Stony Brook University
Alberto Perez of the University of Florida said: "This work highlights how the integrated and streamlined tools developed in the laboratory can be used in conjunction with experimental data to advance our understanding of structural biology
The team’s findings are published on the cover of the current "Cell Press" magazine
Just cold
A series of modern imaging technologies enable researchers to study the key molecules of life, including proteins, nucleic acids, and even individual molecules
Like other forms of electron microscopes, cryo-electron microscopes use electron beams to replace the photons used to illuminate samples in traditional optical microscopes
Cryo-EM is one of the three methods used in structural biology research, which is combined with x-ray crystallography and nuclear magnetic resonance spectroscopy (NMR)
Cryogenic electron microscope has matured
Since the sample does not need to be crystallized and can be studied in its natural surrounding environment, cryo-electron microscopy has made considerable progress in imaging large and complex biomolecules
Overfitting the original data to the structural model may produce inaccuracies
.
In contrast, the new method makes no assumptions about the final molecular structure, except for known constraints
.
By generating the most unbiased structure, this maximum entropy method can help researchers fill in the gaps in the structure determination process and better explain the contributions of various conformations that may exist at very low frequencies
.
To fully understand biomolecules like proteins, it is necessary to simultaneously determine the structure of all relevant states that these molecules can assume
.
Simply imagine trying to make a model to illustrate the behavior of a boy who stands still for an hour, except for the occasional brief movements of his arms and legs
.
On average, there is no change, and the resulting boy model will consist of a static, still image
.
On the other hand, the maximum entropy method will allow all different gestures, no matter how short, to contribute to the final image, producing a more accurate representation
.
This new study provides six examples of carefully folded proteins of different sizes, including large membranes and multi-domain systems
.
This result emphasizes the ability of the maximum entropy statistical software package (called CryoFold) to discover molecular integration, including rare low-probability structures that have been experimentally verified and identified as functionally related
.
The maximum entropy technology can be combined with existing data fitting methods to convert low-resolution data into a high-resolution, high-confidence three-dimensional structure in the iterative process
.
These advances are helping cryo-electron microscopy to achieve its full potential by characterizing the entire conformational landscape of proteins and other important biomolecules
.
"This work integrates multiple physics-based methods to refine protein structure data from cryo-electron microscopy, providing not a static picture of a protein, but a collection of structures, which represent the correct, dynamic properties of the protein," Chitrak Gupta said , Co-author CASD researcher and SMS
.
Article title
CryoFold: Determining protein structures and data-guided ensembles from cryo-EM density maps