p53 is a protein with marginal stability. Its transcriptional functions are often inactivated by single missense mutations, shown to be associated with half of all human cancers. Here, we aim to design stable functional p53 mutants. We target loop L1, one of the most mobile structural motifs in the p53 core domain (p53C). Specifically, we selected Ser116 in the middle of loop L1 and mutated it to 14 other amino acids. All resulting mutants were subjected to molecular dynamics simulations, revealing a wide spectrum of stabilities. Among these, mutant S116M displayed a remarkable stability, with a structural deviation comparable to that of the experimental quadruple mutant M133L/V203A/N239Y/N268D that is thermodynamically more stable than that of the wild type by 2.6 kcal/mol. Structural analysis showed that the high stability of the S116M mutant was indeed due to the preservation of the p53C loop L1 conformation and the reduction of mobility in that region. The differential stabilities conferred by the single mutations are rationalized based on the geometries and chemical properties of the side chains introduced into this site. Linearity (i.e., nonbranched), moderate size, and balanced hydrophobic and hydrophilic properties of the side chain are crucial to the stabilizing effect of the residue substitutions.