To characterize the catalytic mechanism for zinc-dependent histone deacetylases (HDAC), we have carried out d. functional theory (DFT) QM/MM studies on the deacetylation reaction catalyzed by a histone-deacetylase-like protein (HDLP). The calcn. results do not support the previous mechanistic hypothesis, but suggest a lower protonation state for the active site as well as a 4-fold zinc coordination during the reaction process. To characterize such mechanistic difference is not only significant for our fundamental understanding of its inner workings but also crucial for the design of HDAC inhibitors. [on SciFinder (R)]