A critical view on conservative mutations

By analysing the surface composition of a set of protein 3D structures, com plemented with predicted surface compositional information for homologous p roteins, we have found significant evidence for a layer composition of prot ein structures. In the innermost and outermost parts of proteins there is a net negative charge, while the middle has a net positive charge. In additi on, our findings indicate that the concept of conservative mutation needs s ubstantial revision, e.g. very different spatial preferences were round for glutamic acid and aspartic acid. The alanine screening often used in prote in engineering projects involves the substitution of residues to alanine, b ased on the assumption that alanine is a 'neutral' residue. However, alanin e has a high negative correlation with all but the non-polar residues. We t herefore propose the use of, for example, serine as a substitute for the re sidues that are negatively correlated with alanine.