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PubMed1985

Conformational analysis of environmental agents: use of X-ray crystallographic data to determine molecular reactivity.

This paper explores the use of crystallographic techniques as an aid in understanding the molecular reactivities of a number of agents that are of concern to pharmacologists and toxicologists. The selected examples demonstrate the role of structural data in the determination of absolute configuration, configurational flexibility and active-site topology for a reactive species. For example, the role of absolute stereochemistry in understanding synthetic pyrethroid structure-activity relationships is shown from analysis of their crystal structures; conformational flexibility among DDT analogues, and the importance of conformational and electronic properties in phenylalkanoic acid herbicides are shown from systematic analysis of their crystal structures; and interpretation of active-site stereochemistry is made by study of computer modeling of enzyme inhibitors in the active sites of related protein crystal structures. Thus, the observed patterns in conformational flexibility and their resultant effects on substrate pharmacological profile can be interpreted in understanding the molecular level events that influence biological reactivity.

Crystallography↗
PubMed2003

Tork: Conformational analysis method for molecules and complexes.

A conformational search method for organic molecules and bimolecular complexes is presented. The method, termed Tork, uses normal-mode analysis in bond-angle-torsion coordinates and focuses on a key subset of torsional coordinates to identify natural molecular motions that lead the initial conformation to new energy minima. New conformations are generated via distortion along these modes and their pairwise combinations, followed by energy minimization. For complexes, special treatment is accorded to the six coordinates that specify the position and orientation of one molecule relative to the other. Tests described here show that Tork is highly efficient for cyclic, acyclic, and mixed single molecules, as well as for host-guest complexes.

Algorithms↗
PubMed1998

Conformational analysis of the 20-residue membrane-bound portion of melittin by conformational space annealing.

The conformational space of the 20-residue membrane-bound portion of melittin has been investigated extensively with the conformational space annealing (CSA) method and the ECEPP/3 (Empirical Conformational Energy Program for Peptides) algorithm. Starting from random conformations, the CSA method finds that there are at least five different classes of conformations, within 4 kcal/mol, which have distinct backbone structures. We find that the lowest energy conformation of this peptide from previous investigations is not the global minimum-energy conformation (GMEC); but it belongs to the second lowest energy class of the five classes found here. In four independent runs, one conformation is found repeatedly as the lowest energy conformation of the peptide (two of the four lowest energy conformations are identical; the other two have essentially identical backbone conformations but slightly different side-chain conformations). We propose this conformation, whose energy is lower than that found previously by 1.9 kcal/mol, as the GMEC of the ECEPP/3 force field. The structure of the proposed GMEC is less helical and more compact than the previous one. It appears that the CSA method can find several classes of conformations of a 20-residue peptide starting from random conformations utilizing only its amino acid sequence information. The proposed GMEC has also been found with a modified electrostatically driven Monte Carlo method [D. R. Ripoll, A. Liwo, and H. A. Scheraga (1998) "New Developments of the Electrostatically Driven Monte Carlo Method: Test on the Membrane-Bound Portion of Melittin," Biopolymers, Vol. 46, pp. 117-126].

Algorithms↗
PubMed1994

Conformational analysis of two cyclic analogs of angiotensin: implications for the biologically active conformation.

Conformations of two cyclic analogs of angiotensin (Asp1-Arg2-Val3-Tyr4-Val/Ile5-His6-Pro7-Phe8, AT), cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT, were studied, independently employing two complementary techniques, energy calculations and NMR measurements in DMSO solution. NMR data were indicative of well-defined solution conformations for the cyclic moieties of cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT, including the phi values for the Cys3/HCys3 and Tyr4 residues, as well as the chi 1 value for the Tyr4 residue. Solution conformations for the exocyclic linear parts of both molecules cannot be described by the NMR data with the same precision. At the same time, independent energy calculations revealed the same conformations of cyclic moieties of cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT among low-energy conformers for both peptides. Moreover, the same conformations are compatible with the model of AT receptor-bound conformation (Nikiforovich & Marshall, 1993), which assumes the particular spatial arrangement of aromatic moieties of Tyr4, His6, and Phe8 residues and the C-terminal carboxyl. These conformers of cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT contain "an open turn" in the backbone of the Tyr4-Val5 residues, instead of the earlier proposed beta-like reversal, thus confirming the suggestion that the conformation(s) ensuring binding of AT analogs with specific receptors should not be described in terms of a unique backbone conformer.

Amino Acid Sequence↗
PubMed1978

Conformational analysis of pyridoxal Schiff's bases. Nuclear magnetic resonance studies of the conformations about the C4-C4', Calpha-Cbeta, and N-Calpha bonds of the pyridoxal Schiff's bases of amino acids.

The solution conformations of a series of pyridoxal-amino acid Schiff's bases were analyzed using 13C and 1H nuclear magnetic resonance techniques. The 13C--1H coupling constants were assigned based on model compounds and isotopic labeling. The predominant conformation of the the C4--C4' bond was found to be "cis" based on nuclear Overhauser effect (NOE) measurements and the "simultaneous" upfield shift of both H4' and H5' in the Schiff's bases of aromatic amino acids. Going from the monoanion (pD 8.2) to the dianion (pD 12.3), changes in these two effects suggested an increasing contribution of the "trans" conformer. The conformation of the N--Calpha bond was found to be approximately the same for all the Schiff's bases studied based on the long-range coupling constants 3J(C4'--Halpha) of these compounds, and the NOE studies indicate that there is a close spatial relationship between H4' and Halpha. The conformations of the Calpha--Cbeta bond of the Schiff's bases of aromatic amino acids were determined by stereospecific deuterium labeling at the beta position. A pi--pi interaction between the aromatic ring and the pi system of pyridoxal was observed which disappeared upon saturation of the aromatic ring.

Amino Acids↗
PubMed1996

Development of Molecular Mechanics Torsion Parameters for alpha,beta-Cyclopropyl Ketones and Conformational Analysis of Bicyclo[m.1.0]alkan-2-ones.

Conformations of cyclopropyl methyl ketone have been studied using ab initio methods in an effort to quantify the effects of conjugative overlap between the cyclopropane ring and an adjacent ketone carbonyl. Results were comparable with previous experimental and theoretical studies. Cyclopropyl methyl ketone exhibits a global energy minimum in the s-cis conformer and a local energy minimum near the s-trans conformer. The potential energy curve obtained was used to derive torsion parameters which were employed in molecular mechanics studies of the conformations of the set of bicyclo[m.1.0]alkan-2-ones having larger ring sizes from five- to 16-membered. Similar conformations for the cyclopropyl ketone substructure are observed for all the medium and large ring systems examined. Possible synthetic ramifications of local conformational anchoring by this functional group array are discussed.

Journal Article↗
PubMed1988

Conformational analysis of optically active phenylethylamines and phenylimidazolines.

Conformational and structural features of phenethylamine and phenylimidazoline derivatives with alpha-adrenergic activity have been studied by MNDO and PCILO methods. From the calculated conformational energy maps, we conclude that phenethylamines exhibit an extended conformation, while the phenylimidazolines adopt a position intermediate between that of corresponding extended and folded conformations. We conclude that the phenethylamines interact with classical Easson-Stedman sites, while the phenylimidazolines interact with a different site. Both phenethylamines and phenylimidazolines show similar requirements for a cationic recognition site.

Chemical Phenomena↗
PubMed1995

Conformational analysis of the lipophilic antifolate trimetrexate.

The conformational properties of the lipophilic antifolate trimetrexate (TMQ) were calculated and compared to the structurally-analogous prototypical antifolate methotrexate (MTX) using both empirical force-field and AM1 quantum mechanical methods. The conformational preferences of TMQ and MTX are diametrically opposed with respect to the bridge-system set of torsion angles tau 1, tau 2: TMQ prefers gauche, trans while MTX prefers approximately trans, gauche. These predictions are consistent with the observed crystal structures of TMQ (i.e., tau 1 = 79 degrees, tau 2 = 178 degrees) and of DHFR-bound MTX (i.e., tau 1 = -157 degrees, tau 2 = 57 degrees in L. casei). The crystal structure of MTX.4H2O deviates from this pattern with tau 1 closer to cis (i.e., 39 degrees) than the predicted trans, yet this near-cis conformation is driven by intermolecular hydrogen-bonding and electrostatic forces operative in the MTX crystal. As a consequence of these strong intermolecular forces, MTX incurs 1.8 kcal/mole in conformational-strain energy in its crystalline form. In contrast, TMQ experiences virtually no conformational strain in its crystalline form. This disparity is attributed to two distinctions between TMQ and MTX: (i) MTX crystallizes as a zwitterion while TMQ crystallizes as the free base, and (ii) the hydrophilic glutamate tail in MTX is replaced by three lipophilic trimethoxy groups in TMQ. The corresponding conformational-strain energy of DHFR-bound MTX is 2.0 kcal/mole while that of DHFR-bound TMQ is only 0.65 kcal/mole based on the assumption that the latter adopts the same bridge conformation as the former. This cost in conformational-strain energy for TMQ and MTX is paid at the expense of their respective free energies of binding of DHFR. Consequently, the present study offers the possibility of designing a new class of antifolates which are conformationally strain-free when bound to DHFR and thereby more effective as chemotherapeutic agents.

Antineoplastic Agents↗
PubMed2002

P-chiral oligonucleotides. 2D Roesy NMR assignment of absolute configuration at phosphorus and conformational analysis of 5'-O-monomethoxytrityl-(2'-O-deoxyribonucleoside) 3'-O-[O-(4-nitrophenyl)]methanephosphonates.

Fast and simple methodology for the assignment of the absolute configuration at the phosphorus atom in diastereomerically pure Rp and Sp 5'-O-monomethoxytrityl-2'-O-deoxynucleoside 3'-O-(O-4-nitrophenyl) methanephosphonate (3) was established. The method utilizes 2D ROESY NMR and can be used for the stereochemical analysis of other P-chiral mononucleotides. Configurational analysis shows that the major conformation of the sugar residue in 3 is of the S (South) type. This study will facilitate synthesis of stereoregular methylphosphonate oligonucleotide analogues via the transesterification method.

Magnetic Resonance Spectroscopy↗
PubMed1985

Conformational analysis of erythrosine B (FD&C Red No. 3) and its comparison with thyroid hormone structures.

Erythrosine B, also known as FD&C Red No. 3, is a tetraiodofluorescein dye that is widely used as a biological stain and color additive in food and drugs. Recent data show that erythrosine B and Rose Bengal, its polychlorophenyl derivative, are potent inhibitors of both 5'-T4 and 5-T4 monoiododeiodinase activity. However, fluorescein, the nonhalogenated parent compound, has no effect on deiodinase activity. The X-ray crystal structure of erythrosine B was determined to elucidate the structural basis for its competition with T4 for its hormone protein binding sites. These structural results show that the dye crystallizes as a free acid-ethanol solvate. The relative orientation of the benzoic acid and xanthine moieties is nearly perpendicular, similar to that observed in the structure of fluorescein. As frequently noted in thyroid hormone structures, there are short I...I and I...O contact distances in this structure. Because of the symmetric iodophenolic substitution pattern of the xanthine ring, there will always be one iodophenolic ring that is not homologous with the thyroid hormone structure. Therefore, this analysis suggests that the best conformational homology is achieved when the dye phenolic ring is matched with that of a skewed thyroid hormone structure.

Binding Sites↗
PubMed1992

The cholesterol-side-chain-cleaving cytochrome P450 spin-state equilibrium. 2. Conformational analysis.

We have confirmed and characterised structurally the enzyme conformational changes deduced from the preceding thermodynamic analysis of the adrenal mitochondrial cholesterol-side-chain-cleaving cytochrome P450 spin-state equilibrium. The spin-transition kinetics following rapid pH jumps were multiphasic in aqueous buffer and biphasic in the presence of 35% ethylene glycol. The activation energy between -2 degrees C and 30 degrees C of both phases was exceptionally high (Ea = 147 kJ.mol-1), suggesting the involvement of large-scale conformational changes. The pH and temperature effects on the CD spectrum show that the enzyme is in equilibrium between at least two conformations which are predicted by the thermodynamic model, but which are not directly correlated to the spin state. The CD changes between 260 nm and 280 nm indicate that the conformation prevailing at high temperatures is characterised by a decreased polarity of the tyrosine environments; the changes between 200 nm and 250 nm suggest furthermore a 4% decreased protein helical content.

Adrenal Cortex↗
PubMed2004

Conformational analysis of drug-like molecules bound to proteins: an extensive study of ligand reorganization upon binding.

This paper describes a large-scale study on the nature and the energetics of the conformational changes drug-like molecules experience upon binding. Ligand strain energies and conformational reorganization were analyzed with different computational methods on 150 crystal structures of pharmaceutically relevant protein-ligand complexes. The common knowledge that ligands rarely bind in their lowest calculated energy conformation was confirmed. Additionally, we found that over 60% of the ligands do not bind in a local minimum conformation. While approximately 60% of the ligands were calculated to bind with strain energies lower than 5 kcal/mol, strain energies over 9 kcal/mol were calculated in at least 10% of the cases regardless of the method used. A clear correlation was found between acceptable strain energy and ligand flexibility, while there was no correlation between strain energy and binding affinity, thus indicating that expensive conformational rearrangements can be tolerated in some cases without overly penalizing the tightness of binding. On the basis of the trends observed, thresholds for the acceptable strain energies of bioactive conformations were defined with consideration of the impact of ligand flexibility. An analysis of the degree of folding of the bound ligands confirmed the general tendency of small molecules to bind in an extended conformation. The results suggest that the unfolding of hydrophobic ligands during binding, which exposes hydrophobic surfaces to contact with protein residues, could be one of the factors accounting for high reorganization energies. Finally, different methods for conformational analysis were evaluated, and guidelines were defined to maximize the prevalence of bioactive conformations in computationally generated ensembles.

Drug Design↗