Insights into the effects of mutations on Cren7-DNA binding using molecular dynamics simulations and free energy calculations

A novel, highly conserved chromatin protein, Cren7 is involved in regulating essential cellular processes such as transcription, replication and repair. Although mutations in the DNA-binding loop of Cren7 destabilize the structure and reduce DNA-binding activity, the details are not very clear. Focusing on the specific Cren7-dsDNA complex (PDB code 3LWI), we applied molecular dynamics (MD) simulations and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations to explore the structural and dynamic effects of W26A, L28A, and K53A mutations in comparison to the wild-type protein. The energetic analysis indicated that the intermolecular van der Waals interaction and nonpolar solvation energy play an important role in the binding process of Cren7 and dsDNA. Compared with the wild type Cren7, all the studied mutants W26A, L28A, and K53A have obviously reduced binding free energies with dsDNA in the reduction of the polar and/or nonpolar interactions. These results further elucidated the previous experiments to understand the Cren7-DNA interaction comprehensively. Our work also would provide support for an understanding of the interactions of proteins with nucleic acids.