Computational Investigations of Changes in Protein Structure Caused by Single Amino Acid Mutations

Variations in the amino acid sequences of proteins can alter their native folds, which can have deleterious effects on protein function. While there has been much success in computational prediction of experimental protein structures, these prediction methods are inaccurate when applied to predicting the structure of mutated proteins. To determine the effects of single amino acid mutations on protein structure, we first curated a dataset of x-ray crystal structures containing multiple unique structures of the wildtype and the structures of single amino acid mutants. We calculate the root-mean-square differences  in the separations between neighboring residues for corresponding residues in the wildtype and mutant. By comparing the magnitude of the structural perturbations  between the wildtype and mutant structures to that for duplicate wildtype structures, we find that on average the magnitudes of the structural perturbations decrease as the sequence and spatial distance from the mutation site increase. Our analysis also shows that size of the structural perturbation correlates with changes in the solvent accessible surface area and charge at the site of the mutation. In future studies, we will develop models to predict the effects of mutations on protein structures.