Scientists reveal the secret of the enzyme without an arginine fingers, which can effectively transmit cellular signals

Guanosintraphosphate (GTP) is one of the basis nucleotides that allow RNA molecules to assemble at the DNA matrix. It is also a source of energy in various biological reactions, such as protein synthesis, and is involved in specific cell signaling processes. In the latter case, special enzymes, so-called small GTPases, remove a fragment of the phosphate nucleotide “tail”, transforming the guanosine triphosphate into a guanosine diphosphate (GDF). Without this support, the speed of reaction is very low, but with the GAP protein activator, it happens almost five times faster.

“System failures can cause cancer developing and metastasizing, that’s why this system is being actively studied. Studies often use small Ras GTPase taken from rat sarcoma. In the complex of this protein and its accelerator, the "arginine finger" plays a crucial role - the amino acid residue of arginine, located in the GAP protein accelerator which penetrating the active center of GTPase as a result of the formation of their complex. This residue is critical for accelerating the GTP hydrolysis reaction. Another GTPase from this group, Ran, interacts with its assistant with the same acceleration, but there are no "arginine fingers" in this process. We decided to examine the secret of its work”, - says Maria Khrenova, the Head of Molecular Modelling Group of the Research Centre of Biotechnology RAS

Together with colleagues from the Lomonosov Moscow State University and Institute of Biochemical Physics named after N.M. Emanuel RAS (IBCP RAS), employees of the Research Centre of Biotechnology RAS modeled the interaction of GTPase Ran with the corresponding protein activator and the whole reaction of this complex with GTP. The simulation was performed using quantum and molecular mechanics methods: it allows to describe the part of the system where the chemical reaction takes place with the quantum chemistry laws (where the molecule is considered as nuclei and electrons). The rest of the protein complex is described with the classical model (the molecule considered as a set of bonded atoms). The movement of the fragments of the system and the state in which they are “fixing" is determined by maximums and minimums of energy. Metaphorically, they are going through rough ground, basically an energy map. So they’re going up a hill, for example, to break the chemical bond, and going down to the bottom when, for example, a new bond is formed.

Based on these principles, the authors simulated GTP hydrolysis processes step by step. The simulation included the representation of Ran behavior without any help from the protein. It turns out the secret of the complex is that the activator is needed to clamp down the active center of the GTPase. The result is a cavity in which the amino acids and water molecules responsible for the reaction, which are inevitably released from the environment, are located most conveniently. Thanks to this Ran enzyme and its assistant do not need “arginine fingers" and not losing efficiency in comparison with other members of the family.

“Understanding the GTPase mechanism during the hydrolysis process will help in cancer research. Many specific drugs are designed to block either the active centers or prevent contact between the enzyme and its assistant. Perhaps our discovery will form the basis of the development of such a drug", - says Maria Khrenova.