A computer simulation method to obtain the intermediate state structure of G protein-coupled receptors

Abstract

The invention provides a method for obtaining the intermediate state structure of G protein-coupled receptors by computer simulation. The method combines targeted molecular dynamics simulation and conventional molecular dynamics simulation to obtain G protein-coupled receptors from an inactive state to an active state. Structure of the intermediate state of a G protein-coupled receptor during the activation state. The method of the present invention has a wide range of applications, is simple and easy to implement, saves time and computer resources, and can simulate the motion trajectory of the research system from the initial state to the final state in a short time, greatly reducing the simulation time and reducing the impact on the computer. Performance requirements; Compared with the experimental macroscopic observation, the present invention is convenient to study the motion change of the system from the atomic level, and can overcome the simulation time problem from the initial state to the final state, and observe the entire change between the two states process.

Description

technical field [0001] The invention belongs to the technical field of computer simulation of G protein-coupled receptor structure, and in particular relates to a method for obtaining the intermediate state structure of G protein-coupled receptor by computer simulation. Background technique [0002] G protein-coupled receptors (GPCRs) are one of the largest membrane protein families in the human body and are an important class of drug targets. About 30% of the drugs on the market use GPCRs as drug targets, so the research on their structure and function has become a International research hotspot. Since GPCR is a membrane protein, it is very difficult to analyze its structure by experimental methods. At present, the receptor structures obtained by experimental techniques such as X-ray crystallization are very limited, and most of them are stable inactive static structures, with only a small amount of activity. However, relying on the static structure of these experimental c...

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Problems solved by technology

Since GPCR is a membrane protein, it is very difficult to analyze its structure by experimental methods. At present, the receptor structures obtained by experimental techniques such as X-ray crystallization are very limited, and most of them are stable inactive static structures, with only a small amount of activity. However, relying on the static structure of these experimental crystals cannot effectively obtain the dynamic process of its signal function

GPCR activation is accompanied by a series of large structural rearrangements, and important intermediate states will be generated in the receptor structural rearrangement. These intermediate states have important functions in its signal transduction, but these intermediate states exist for a very short time , It is difficult to capture by experimental technical methods. The absence of these intermediate structures obviously limits the research on the structure and function of GPCRs, making it difficult to elucidate the activation mechanism of GPCRs and design drugs.

[0003] The computer simulation method (molecular dynamics simulation) can obtain the microstructure of the protein function change process in an extremely fast time at the atomic level, which can just make up for these experimental deficiencies, but the GPCR activation process occurs in the time range of milliseconds and seconds , using the conventional molecular dynamics simulation (CMD) method (the process is shown in the attached figure 1 shown) This time scale is difficult to achieve on current computer resources, and it is difficult to obtain all the structures in the changing process

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