“…It has also been found that SPro could also be introduced into proteins via misincorporation of SPro in place of proline during protein synthesis [ 23 ]. SPro forms part of the structure of kynostatin 272 (KNI-272) a pentapeptide mimic containing two sulfur atoms that acts as a conformationally constrained inhibitor of HIV protease [ 24 , 25 , 26 , 27 , 28 ] and for which the role of the SPro residue in the conformation has been discussed [ 26 , 27 ]. In the same context, it forms part of the structure of possible prolyl-oligopeptidase inhibitors of use in the prevention of Alzheimer’s disease and senile dementia [ 29 ].…”
Section: Introductionmentioning
confidence: 99%
“…SPro as generally occur for amino acids crystalizes in its zwitterionic form and the studies of its structure by X-ray diffraction yield to a single form with the carboxyl group adopting an equatorial arrangement and the ring adopting an S γ - endo bent form [ 30 ]. The conformation adopted by SPro residues in KNI-272 for example was discussed based on two possible endo or exo forms of the ring and the cis-trans amide bonds equilibrium [ 26 , 27 ], as occur for Pro [ 4 ] residues. The same equilibria reinforced by hydrogen bonding between the acid and imino group exists in isolated Pro leading to four conformers [ 31 , 32 ].…”
The broadband rotational spectrum of jet-cooled laser-ablated thioproline was recorded. Two conformers of this system were observed and identified with the help of DFT and ab initio computations by comparison of the observed and calculated rotational constants and 14N quadrupole coupling constants as well as the predicted energies compared to the observed relative populations. These conformers showed a mixed bent/twisted arrangement of the five-membered ring similar to that of the related compound thiazolidine with the N–H bond in axial configuration. The most stable form had the COOH group in an equatorial position on the same side of the ring as N-H. The arrangement of the C=O group close to the N-H bond led to a weak interaction between them (classified as type I) characterized by a noncovalent interaction analysis. The second form had a trans-COOH arrangement showing a type II O–H···N hydrogen bond. In thioproline, the stability of conformers of type I and type II was reversed with respect to proline. We show how the conformation of the ring depends on the function associated with the endocyclic N atom when comparing the structures of isolated thioproline with its zwitterion observed in condensed phases and with peptide forms.
“…It has also been found that SPro could also be introduced into proteins via misincorporation of SPro in place of proline during protein synthesis [ 23 ]. SPro forms part of the structure of kynostatin 272 (KNI-272) a pentapeptide mimic containing two sulfur atoms that acts as a conformationally constrained inhibitor of HIV protease [ 24 , 25 , 26 , 27 , 28 ] and for which the role of the SPro residue in the conformation has been discussed [ 26 , 27 ]. In the same context, it forms part of the structure of possible prolyl-oligopeptidase inhibitors of use in the prevention of Alzheimer’s disease and senile dementia [ 29 ].…”
Section: Introductionmentioning
confidence: 99%
“…SPro as generally occur for amino acids crystalizes in its zwitterionic form and the studies of its structure by X-ray diffraction yield to a single form with the carboxyl group adopting an equatorial arrangement and the ring adopting an S γ - endo bent form [ 30 ]. The conformation adopted by SPro residues in KNI-272 for example was discussed based on two possible endo or exo forms of the ring and the cis-trans amide bonds equilibrium [ 26 , 27 ], as occur for Pro [ 4 ] residues. The same equilibria reinforced by hydrogen bonding between the acid and imino group exists in isolated Pro leading to four conformers [ 31 , 32 ].…”
The broadband rotational spectrum of jet-cooled laser-ablated thioproline was recorded. Two conformers of this system were observed and identified with the help of DFT and ab initio computations by comparison of the observed and calculated rotational constants and 14N quadrupole coupling constants as well as the predicted energies compared to the observed relative populations. These conformers showed a mixed bent/twisted arrangement of the five-membered ring similar to that of the related compound thiazolidine with the N–H bond in axial configuration. The most stable form had the COOH group in an equatorial position on the same side of the ring as N-H. The arrangement of the C=O group close to the N-H bond led to a weak interaction between them (classified as type I) characterized by a noncovalent interaction analysis. The second form had a trans-COOH arrangement showing a type II O–H···N hydrogen bond. In thioproline, the stability of conformers of type I and type II was reversed with respect to proline. We show how the conformation of the ring depends on the function associated with the endocyclic N atom when comparing the structures of isolated thioproline with its zwitterion observed in condensed phases and with peptide forms.
“…Murcko and coworkers (38) argued that the trans conformer of KNI-272 is not inherently more stable than the cis conformation, based upon ab initio studies of small molecules related to KNI-272. However, MM calculations yielded a trans/cis population ratio of 6.0 for KNI-272 in solution.…”
Section: Conformational Analysis Of An Inhibitor Of Hiv-1 Proteasementioning
Efficient, reliable methods for calculating the binding affinities of noncovalent complexes would allow advances in a variety of areas such as drug discovery and separation science. We have recently described a method that accommodates significant physical detail while remaining fast enough for use in molecular design. This approach uses the predominant states method to compute free energies, an empirical force field, and an implicit solvation model based upon continuum electrostatics. We review applications of this method to systems ranging from small molecules to protein-ligand complexes.
“… 1 (a) Structure of KNI-272. (b) Structure of small-molecule fragment of KNI-272, compound 4 from Murcko et al …”
Section: Introductionmentioning
confidence: 99%
“…On the other hand, a quantum chemical study of KNI-272 concluded that its bound conformation is strained. In particular, calculations on a small molecule that models the central Apns−Thp region suggested that one dihedral angle (T1 = ψ Thp ) is strained by 8−13 kJ/mol in the crystal conformation of KNI-272.…”
The compound KNI-272 is a potent, peptide-like inhibitor of HIV protease. Its conformation when complexed
with the protease is close to that which it assumes in its single-molecule crystal. This observation led to the
suggestion that KNI-272 gains affinity by being preorganized for binding. On the other hand, one might well
expect KNI-272 to be flexible because it possesses 15 rotatable bonds. Moreover, a recent ab initio study of
KNI-272 suggests that it is not preorganized because its bound conformation is strained. Here, we use a
novel algorithm to study the conformational distribution of this inhibitor. The results show good agreement
with a recent NMR analysis of KNI-272 in solution. The calculations indicate that KNI-272 in solution occupies
three major conformations, one of which matches the bound conformation and the NMR structure. In addition,
the thioproline amide bond tends to be in the trans conformation found in the complex of KNI-272 with HIV
protease. Further calculations on hypothetical analogues of KNI-272 provide information on the mechanism
of preorganization and indicate that steric interactions among the bulky side chains are of particular importance.
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