Coarse-Grained Modeling And Molecular Dynamics Simulations Of Conformational Changes In ABC Transporters

ATP-Binding Cassette(ABC)exporters use energy from ATP binding or/and hydrolysis to actively transport a wide variety of substrates across the lipid membrane by alternating between inward-facing(IF)and outward-facing(OF)states of the transmembrane domains(TMDs),which plays a critical role in the process of cell life.So far,there are have been several controversies that the detailed mechanisms of the conformational transition in ABC transporters are not completely clear for a long time,albeit there has been abundant biological experimental researches.This article presents an introduction to the topic of coarse-grained modeling of ABC transporter structures and dynamics,for example in the case of Yeast Atm1 ABC exporters.And the potential of mean force(PMF)is calculated to explain transport mechanisms.As the process of transport is implicated in large-scale conformational changes in ABC exporters,it is an unsolved problem that all-atom MD approach is to discover transport mechanisms in the field of computational chemistry.In this article,coarse-grained molecular dynamics(CG-MD)simulations combined with the umbrella sampling method are applied to yeast mitochondrial ABC transporter Atm1 as a prototype in the presence of the lipid membrane and explicit water molecules.There is a trajectory coordinate designed to monitor the conformational changes in the protein,and then the PMF is calculated along the trajectory coordinate to acquire the detailed mechanisms.The results show that a highly collaborative manner derived from NBDs(nucleotide binding domains)and TMDs results in the timing of the gating motions for the unidirectional transport of substrates.This article elaborates on the transport mechanisms in yeast mitochondrial ABC transporter Atm1.Therefore,it is possible to solve the controversial problems in ABC research field.The study of the transport mechanisms of ABC protein will play a positive role in the targeted drug design and shorten the drug development cycle.ABC transporters can mediate the efflux of drugs by cells,thus affecting the kinetic processes of many drugs in vivo.In this article,the graph neural network is used to study the pharmacokinetic properties,including the prediction of drug absorption,distribution,metabolism,excretion and toxicity(ADMET)properties,so as to reduce the probability of drug development failure and provide the basis for new drug development.