生物化学与生理学：开放获取

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Structural Effects of Leigh Syndrome Mutations on the Function of Human Mitochondrial Complex-I Q module

Tulika M Jaokar, Ranu Sharma and Suresh CG

The Q module of the human mitochondrial Complex-I (NADH:ubiquinone oxidoreductase) comprises of four core protein subunits: NDUFS2, NDUFS3, NDUFS7 and NDUFS8. It is an intermediate unit, connecting the dehydrogenase domain (N module) and the membrane arm (P module) of the L shaped mitochondrial Complex-I. Its role is to transfer electrons from N module to the P module. Mutations in the subunits of this module are reported to be associated with Leigh syndrome, a neurological genetic disorder. The Q module of human mitochondrial Complex-I is modelled based on the crystal structure of Thermus thermophilus Complex-I. The structural ramifications of the documented Leigh syndrome mutations were studied in silico, using molecular dynamics simulations. Although the mutations caused minimum perturbation to the overall secondary structure, the root mean square fluctuations of certain segments were substantial, especially those in the loop regions. The mutations affected the hydrogen bonded interactions, solvent accessible area, and the observed radius of gyration to various extents. The cumulative effect of all these changes on the formation of complex assembly is reflected in the observed unfavourable energy variations, instability of subunit association, and a reduced affinity for substrates, such as ubiquinone. Thus, our analysis indicates that Leigh syndrome mutations lead to formation of structurally and functionally defective complex, which in turn results in disease phenotype.