Nature: building protein molecular "search network" by computer

It is now a reality to design proteins that can recognize and interact with biological small molecules by computer Scientists have successfully constructed a protein molecule using computer design in the laboratory, which can be programmed to combine three different steroids The "search network" can recognize and combine protein molecules of small molecules, which may be more widely used in medicine and other fields "This is an important step toward building proteins that can be used as biosensors or molecular sponges," said Christine E tinberg, one of the lead researchers and a postdoctoral fellow in biochemistry at the University of Washington Nature: building protein molecular "search network" by computer
Christine E tinberg is working In a September 4 paper in nature, the authors describe in detail the methods used Giovanna ghirlanda from Arizona State University published a review on this nature paper, "computational biology: a recipe for living binding proteins" "Developing this approach to design proteins with ideal recognition sites could be revolutionary," he wrote Because cell processes such as cell crosstalk, gene product production and enzyme operation all depend on molecular recognition The team overcame previously unsolved problems in building precise protein small molecule interfaces In early efforts, scientists have been trying to solve the problem of inconsistency between computer graphics and real molecular structure In completing the study, the researchers learned the general principles of designing attractive small molecule binding proteins Their findings show that it is possible to construct some binding proteins that can satisfy many medical, industrial and environmental applications For example, using a properly programmed protein in medical diagnosis may be able to detect some biomolecules that only exist in a specific disease state, such as the early stage of cancer It may eventually be possible to make other types of protein molecules that can be used to treat drugs or drug overdoses Tinberg explained that at present, the main ways to generate new small molecule binding proteins are to immunize animals to generate antibodies against a target protein, or to control the evolution of proteins in the laboratory to enhance their affinity for the desired small molecules "Neither approach can fully control the interaction associated with binding." In designing the molecule, the team tried to replicate the properties of a naturally occurring protein binding site The scientists also programmed the necessary protein-molecule interactions by adjusting the conformation and orientation of binding sites Using a computer tool called Rosetta, the researchers created a new protein that binds to the steroid digoxigenin After using computers to generate multiple digitalis glycoside binders, the researchers selected 17 to synthesize in the laboratory Laboratory tests have allowed researchers to focus on the protein they named dig10 Further observation showed that, as the researchers expected, the binding activity of the protein was indeed mediated by a computer-designed interface In order to improve their overall design method, the researchers also used a new generation of deep gene sequencing method to mark the impact of each amino acid molecular component on the binding fitness Using this method, they can find out how different genetic variations affect the binding ability of design proteins This map of binding fitness enables researchers to increase the binding affinity of the design protein to the picomorphic level X-ray crystallography shows that the actual structure of the two protein molecules and the computer design match up to the atomic level Therefore, the mismatch between the design model and the protein produced in the laboratory is no longer a difficult obstacle for researchers to overcome According to the researchers, through continuous improvement of methods and feedback from experimental results, computer protein design provides an increasingly powerful method for the production of synthetic biological small molecule receptors, therapeutic scavengers of toxic compounds, and powerful binding domains for diagnosis.