Computational Microscopy: Using Simulations to Decode Infrared Vibrations

BPJ_112_1.c1.inddHeterotrimeric G-proteins are molecular switches that are omnipresent in animal and plant cells. They maintain central physiological processes such as vision, scent, or blood pressure regulation. The signal is determined by a small molecule, Guanosine triphosphate (GTP).  GTP binds to the heterotrimeric protein and thereby switches the signal “on.” The off-switch is maintained by hydrolysis of GTP to GDP and a phosphate moiety.

This central molecular reaction has beenthe focus of research for dozens of years, as the mechanism is highly conserved and leads to a plethora of diseases when disturbed, including cancer.

The cover image for the January 10 issue of the Biophysical Journal shows the GTP molecule bound to the active site of Gi1, one of three subunits of heterotrimeric G-proteins. The image was created using the program Blender. The configuration was obtained from coupled quantum mechanics and molecular dynamics simulations of the protein crystal structure. We used these simulations to obtain a structural interpretation of infrared spectroscopy measurements of the protein. Although infrared spectroscopy yields millisecond temporal and sub-Ångstrom spatial resolution, this information is encoded into infrared spectra that can be hard to interpret. However, a figure like the cover image can help this become easier to understand. By combining simulations with experiments one can use the computer as a microscope with subatomic resolution and directly observe structural and electronic changes. We benchmarked this setup by introducing point mutations at the active site (indicated as sticks in the picture) and comparing experimental and computational spectral changes that were found to be in agreement.

Further simulations elucidated details about the Mg2+ cofactor in the active site (green sphere) and about catalysis of GTP hydrolysis by heterotrimeric G-proteins that can be found in our article.

-Daniel Mann, Udo Höweler, Carsten Kötting and Klaus Gerwert


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