Conformational behavior of α,α‐dialkylated peptides: Ab initio and empirical results for cyclopropylglycine

Abstract

SynopsisThe preferred conformations of model cyclopropylglycine peptides have been investigated by means of ab initio and empirical methods. Empirical computations performed with fixed bond lengths and valence angles using two well-known force fields show that only values of $ I in the ranges k70" k 20" are sterically allowed, and that the C,-conformation corresponds to the absolute energy minimum irrespective of the terminal groups used. Also, ab initio computations give similar results, but suggest greater stabilities for bridge and, especially, extended structures. These discrepancies can be removed, adding to the empirical force field a twofold torsional potential on \c. and using softer steric repulsive potentials. Complete geometry optimization using both ab initio and empirical methods does not affect the relative stabilities of folded conformations, but leads to a further significant stabilization of the fully extended structure via large modifications of some valence angles.

Conformational profile of 1-aminocyclopropanecarboxylic acid

“…In order to solve these diculties an ad hoc incorporation of a twofold torsional potential with a barrier of 4.4 kcal/mol for w was proposed to describe the conformational features of cyclopropane derivatives [17]. This barrier incorporated into the MM2 force ®eld, provides conformations in agreement with experimental observations [17,19]. With regard to the force constants and equilibrium parameters, we reported in a recent work a parametrization for the stretching and bending parameters of cyclopropane [20].…”

“…The stability of the conformations with w = 180°is underestimated. In order to solve these diculties an ad hoc incorporation of a twofold torsional potential with a barrier of 4.4 kcal/mol for w was proposed to describe the conformational features of cyclopropane derivatives [17]. This barrier incorporated into the MM2 force ®eld, provides conformations in agreement with experimental observations [17,19].…”

“…The present results agree with those reported in our previous work [18], where the same three minima were characterized at the HF/6-31G(d) level by geometry optimization of the nine minima that may be anticipated for the potential-energy surface E = E(/, w). Barone et al [17] found a minimum 1.8 kcal/mol above the global minimum at / = )88°, w = )1°at the HF/STO-3G level. Similarly, calculations at the HF/3-21G level [18] characterized a minimum 0.3 kcal/mol above the global minimum at / = )95°, w = 2°.…”

“…With regard to molecular mechanics calculations, Barone et al [17] and Taylor et al [19] pointed out that standard force-®eld parameters cannot properly account for the conformational preferences of Ac 3 c. Speci®cally, standard force ®elds display three important de®ciencies:…”

Rapid synthesis of cyclopropane-dipeptide analogues

“…Such compounds, as well as their synthetic counterparts, have been shown to be either particularly valuable tools for the determination of structure-activity relationships [5][6][7][8][9][10][11] or they are good enzyme inhibitors [12][13][14], some having even promising therapeutic effects in humans [15]. As a consequence, there is a special need to design synthetic methods that can quickly provide cyclopropane(-substituted) peptides (or analogues) for evaluation as biological tools or enzyme inhibitors.…”