Cis-trans isomerization of proline in the peptide (his 105-Val 124) of ribonuclease a containing the primary nucleation site

Conformational energy calculations have been carried out to determine the relative stabilities of the C-terminal sequence 105-124 of ribonuclease A, with cis and trans forms, respectively, of Asn 113-Pro 114. The cis form of Pro 114 is the one that occurs in the native protein. This peptide contains the sequence 106-118, which, on the basis of both theoretical and experimental studies, is thought to constitute the primary nucleation site for the folding of ribonuclease A. It is shown that both conformations of the isolated peptide (with Pro 114 in the cis and trans forms, respectively) are of approximately equal stability. Both forms have similar conformations from residues 105-110 and 118-124, while they differ in the bend region involving residues 111-117. Calculations have also been carried out to deduce the possible low-energy paths for the interconversion between the cis and trans forms of both Pro 114 and Pro 117. It is shown that there are two low-energy paths (with a minimum activation energy of 16.5 kcal/mole) for the interconversion of Pro 114. Attractive nonbonded interaction energies stabilize the transition state on these paths. Only one relatively low-energy path (with an activation energy of 18 kcal/mole) could be found for the isomerization of Pro 117, which occur in the trans form in the native protein; in this case, all cis forms have significantly higher energy than the trans form. These calculations thus show that native-like forms for the isolated peptide can exist with Pro 114 in either the cis or the trans form and that these forms are readily interconvertible.