Elucidating Proton-mediated Conformational Changes In An Acid-sensing Ion Channel 1a Through Molecular Dynamics Simulation

Ion channel proteins on the biological membrane are the main components of the nervous system and control the transmembrane transport of ions.In the process of nerve conduction,central nervous system regulation,hormone secretion and other activities of life,they play an important role.In recent years,the research of ion channel proteins tends to study the structure and function.With the development of computer,the method of molecular dynamics simulation provides a powerful method for the dynamic relationship between biological macromolecules and the channel gating,and reveals the essence of protein activity in microcosm.At the same time,it provides important theoretical basis for the corresponding experimental research.Acid-sensitive ion channel 1a(ASIC1a)protein is widely present in the central nervous system and belongs to the Epithelial sodium ion channel / Degenerate protein superfamily member.At the same time,ASIC1 a acts as proton-activated receptor cation channel,contributes to sensory transduction,depression and fear-related behaviors throughout nervous system.In the physiological pathology process,ASIC1 a cause ischemic stroke,pain,anxiety,memory deterioration and other symptoms.So far,ASIC1 a has been studied experimentally,and it is found that the ion channel proteins are mainly controlled the entry of ions by the transmembrane domain.Under acidic conditions,the ion channel gating will be activated and allow ions to pass through.Too much ions pass into the cell interior leading to the cell overload and death.This is what we call acidosis.But how proton mediates the channel gating process still remains elusive.Therefore,we will research the process of the protein domain controlling the channel gating process.Here we report that the ion pore changes at different PH values through molecular dynamics(MD)simulations.The path of long-range conformational changes from the extracellular domain to the transmembrane domain was determined by the method of principal component analysis;further,the correlation network analysis reveals how the interactions between subunits influence the channel gating changes.β1,β2,β10,α6,α7,β11 and β12 are the crucial regions by forming a passageway to regulate the ion pore changes.Our results reveal the process that the extracellular domain remotely regulates the pore changes.Meantime,our researches have improved important information for the design and research of drugs to prevent acidosis.