The mutations of R248 to Trp and Gln in the core domain (CD) of the p53 protein are some of the most common mutations found in human cancer. Although the: mutant 248Q and 248W p53-CDs retain the wild-type conformation and stability, they lack sequence-specific DNA binding and transactivation functions and the ability to suppress cell growth. The structural and energetic bases for the observed loss of DNA binding are unclear as the DNA-free and DNA-bound mutants are not available. Hence, we have generated three-dimensional models of the wild type, 248Q, and 248W p53-CDs, free and bound to DNA, using molecular. dynamics simulations in the presence of explicit water molecules. Based on the simulation structures, the free energies of wild type and mutant p53-CDs binding to DNA have been computed and decomposed into component energies (electrostatic vs van der Waals vs cavity) and contributions from the interface residues. The DNA-free mutant structures were found to be consistent. with antibody-binding and NMR data. The predicted DNA binding losses of both mutants were also in accord with experimental data. The calculations revealed that mutating R248 in the minor groove yielded long-range changes in the major groove DNA-binding interface, and the extent of these changes differs depending on the mutation type. The DNA-binding loss of the 248Q p53-CD mutant is due mainly to the loss of major groove contacts from K120 (located similar to20 A from the mutation site) as well as,unfavorable interactions of D281. In contrast, the DNA-binding loss of the 248W p53-CD mutant is due mainly to the loss of minor groove contacts from the mutant residue itself. It is also due, to a lesser extent, to the loss of major, groove contacts from loop L1 and to the poorer packing of the protein-DNA interface in the 248 W mutant complex relative to the wild-type. The results obtained here are important in deciding the rescue strategy of mutant p53 DNA binding.