Abstract
The role played by the geometric position of each amino acid in the folding process of the immunoglobulin (Ig) variable domain is identified and measured through molecular dynamics simulations of models based on the topology of its native state. This measure allows identifying the parts of the protein that, for geometrical reasons, when mutated, would result in relevant protein stability changes. Simulations were performed without considering the covalent disulfide bond present in most of the Ig domains. The results are in good agreement with site-directed mutagenesis experiments on the folding of intracellular antibodies in which the disulfide bond does not form. We also found agreement with data on amino acid conservation in the Ig variable domain sequences. This indicates a new way for a rational approach to the design of intracellular antibodies more resistant to the suppression of the disulfide bond that occurs in the cytoplasm.