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Human oxidosqualene cyclase(OSC)plays a key role in cholesterol biosynthesis.It can catalyze the linear-chain 2,3-oxidosqualene to form four-rings lanosterol,which is the precursor of cholesterol.As this enzyme functions downstream of cholesterol synthesis,it attracts more and more attention as one novel hypolipidemic target due to its less side-effect.1 The mechanism of OSC,however,is still very controversial in the past half a century.2-4 Herein,state-of-the-art ab initio QM/MM MD simulations with umbrella sampling are applied to investigate this complicated cyclization mechanism.Interestingly,our study reveals that the formation of C and D rings is one near-synchronous reaction from a stable “6-6-5” ring intermediate to another stable state “6-6-6-5” ring.Moreover,the transition state of this concerted reaction presents one “6-6-6” structure motif,while this structure is thought to be one stable intermediate in previous hypothesis.5 Very recently,we are also carried out the two-dimentional umbrella sampling to investigate the A and B rings cyclization.