A new view of missense mutations in α-mannosidosis using molecular dynamics conformational ensembles

The mutation of remote positions on enzyme scaffolds and how these residue changes can affect enzyme catalysis is still far from being fully understood. One paradigmatic example is the group of lysosomal storage disorders, where the enzyme activity of a lysosomal enzyme is abolished or severity reduced. In this work, we analyze molec- ular dynamics simulation conformational ensembles to unveil the molecular features controlling the deleterious effects of the 43 reported missense mutations in the human lysosomal α-mannosidase. Using residue descriptors for protein dynamics, their cou- pling with the active site, and their impact on protein stability, we have assigned the contribution of each of the missense mutations into these three categories. We demon- strate here that the use of conformational ensembles is a powerful approach not only to better understand missense mutations at the molecular level, but to revisit the mis- sense mutations reported in lysosomal storage disorders in order to aid the treatment of these diseases.