Role of native-state topology in the stabilization of intracellular antibodies

The role played by the geometric position of each amino acid in the folding process of the immunoglobulin (Ig) variable domain is identified and measu red through molecular dynamics simulations of models based on the topology of its native state. This measure allows identifying the parts of the prote in that, for geometrical reasons, when mutated, would result In relevant pr otein 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 foldin g of intracellular antibodies in which the disulfide bond does not form. We also found agreement with data on amino acid conservation in the Ig variab le domain sequences. This indicates a new way for a rational approach to th e design of intracellular antibodies more resistant to the suppression of t he disulfide bond that occurs in the cytoplasm.