Method for simulating acquisition of G-protein-coupled receptor intermediate state structure through computer

Abstract

The invention provides a method for simulating acquisition of a G-protein-coupled receptor intermediate state structure through a computer. With the combination of target molecular dynamics simulationand common molecular dynamics simulation, a G-protein-coupled receptor intermediate state structure of a G-protein-coupled receptor in the activation process from a non-active state to an active state is acquired by using the method. The method provided by the invention is wide in application range and is simple and feasible, the time and computer resources are saved, a movement track of a studysystem from a start state to a final state can be simulated within a short time, the simulation time is greatly shortened, and the requirements on computer performance are also reduced; compared withexperimental macroscopic observation, movement change of a system is conveniently studied at the level of atoms, in addition, the problem of simulation time from the start state to the final state isovercome, and the whole change process within the two states can be observed.

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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