Alpha-gamma hybrid peptides that contain the conformationally constrained gabapentin residue: characterization of mimetics of chain reversals

The crystal structures of four dipeptides that contain the stereochemically constrained gamma-amino acid residue gabapentin (1-(aminomethyl)cyclohexaneacetic acid Gpn) are described. The molecular conformation of Piv-Pro-Gpn-OH (1), reveals a beta-turn mimetic conformation, stabilized by a ten atom C[bond]H...O hydrogen bond between the Piv CO group and the pro S hydrogen of the Gpn CH(2)[bond]CO group. The peptides Boc-Gly-Gpn-OH (2), Boc-Aib-Gpn-OH (3), and Boc-Aib-Gpn-OMe (4) form compact, folded structures, in which a distinct reversal of polypeptide chain direction is observed. In all cases, the Gpn residue adopts a gauche,gauche (g,g) conformation about the C(gamma)[bond]C(beta) (theta(1)) and C(beta)[bond]C(alpha) (theta(2)) bonds. Two distinct Gpn conformational families are observed. In peptides 1 and 3, the average backbone torsion angle values for the Gpn residue are phi=98 degrees, theta(1)=-62 degrees, theta(2)=-73 degrees, and psi=79 degrees, while in peptide 2 and 4 the average values are phi=-103 degrees, theta(1)=-46 degrees, theta(2)=-49 degrees, and psi=-92 degrees. In the case of 1 and 3, an intramolecular nine-membered O[bond]H...O hydrogen bond is formed between the C[double bond]O of the preceding residue and the terminal carboxylic acid OH group. All four alpha-gamma dipeptide sequences yield compact folded backbone conformations; this suggests that the Gpn residue may be employed successfully in the design of novel folded structures.     

Glucose orientation and dynamics in alpha-, beta-, and gamma-cyclodextrins

We investigate, using molecular dynamics (MD) computer simulations, the conformational behavior of alpha-, beta-, and gamma-cyclodextrins (CDs). Our analysis of a 30 ns trajectory of CD solution dynamics reveals the underlying conformational behaviours of the CDs that explain their relative flexibility. The distributions of the torsion angles related to the glycosidic linkages, P(phi,psi) were calculated for the three CDs. Most noticeable is the limited range in phi torsion rotations compared with psi rotations for all the CDs. This difference between the three CDs is amplified in the motion and dynamics of their glucose monomers when we monitor their orientational and librational positions relative to the macrocyclic mean plane. The relaxation times of the monomers to their equilibrium orientations follow the pattern gamma-CD > alpha-CD > beta-CD. The root-mean-square deviations of the motion of the monomer centers of mass from the mean macrocyclic planes exhibit the same trend.     

Conformational preference and cis-trans isomerization of 4(R)-substituted proline residues

We report here the conformational preference and prolyl cis-trans isomerization of 4(R)-substituted proline dipeptides, N-acetyl-N'-methylamides of 4(R)-hydroxy-L-proline and 4(R)-fluoro-L-proline (Ac-Hyp-NHMe and Ac-Flp-NHMe, respectively), studied at the HF/6-31+G(d), B3LYP/6-31+G(d), and B3LYP/6-311++G(d,p) levels of theory. The 4(R)-substitution by electron-withdrawing groups did not result in significant changes in backbone torsion angles as well as endocyclic torsion angles of the prolyl ring. However, the small changes in backbone torsion angles phi and psi and the decrease of bond lengths r(Cbeta-Cgamma) or r(Cgamma-Cdelta) appear to induce the increase of the relative stability of the trans up-puckered conformation and to alter the relative stabilities of transition states for prolyl cis-trans isomerization. Solvation free energies of local minima and transition states in chloroform and water were calculated using the conductor-like polarizable continuum model at the HF/6-31+G(d) level of theory. The population of trans up-puckered conformations increases in the order Ac-Pro-NHMe < Ac-Hyp-NHMe < Ac-Flp-NHMe in chloroform and water. The increase in population for trans up-puckered conformations in solution is attributed to the increase in population for the polyproline-II-like conformations with up puckering. The barriers DeltaGct++ to prolyl cis-to-trans isomerization for Ac-Hyp-NHMe and Ac-Flp-NHMe increase as the solvent polarity increases, as seen for Ac-Pro-NHMe. In particular, it was identified that the cis-trans isomerization proceeds through the clockwise rotation about the prolyl peptide bond for Ac-Hyp-NHMe and Ac-Flp-NHMe in chloroform and water, as seen for Ac-Pro-NHMe.     

Structure determination of a peptide model of the repeated helical domain in Samia cynthia ricini silk fibroin before spinning by a combination of advanced solid-state NMR methods

Fibrous proteins unlike globular proteins, contain repetitive amino acid sequences, giving rise to very regular secondary protein structures. Silk fibroin from a wild silkworm, Samia cynthia ricini, consists of about 100 repeats of alternating polyalanine (poly-Ala) regions of 12-13 residues in length and Gly-rich regions. In this paper, the precise structure of the model peptide, GGAGGGYGGDGG(A)(12)GGAGDGYGAG, which is a typical repeated sequence of the silk fibroin, was determined using a combination of three kinds of solid-state NMR studies; a quantitative use of (13)C CP/MAS NMR chemical shift with conformation-dependent (13)C chemical shift contour plots, 2D spin diffusion (13)C solid-state NMR under off magic angle spinning and rotational echo double resonance. The structure of the model peptide corresponding to the silk fibroin structure before spinning was determined. The torsion angles of the central Ala residue, Ala(19), in the poly-Ala region were determined to be (phi, psi) = (-59 degrees, -48 degrees ) which are values typically associated with alpha-helical structures. However, the torsion angles of the Gly(25) residue adjacent to the C-terminal side of the poly-Ala chain were determined to be (phi, psi) = (-66 degrees, -22 degrees ) and those of Gly(12) and Ala(13) residues at the N-terminal of the poly-Ala chain to be (phi, psi) = (-70 degrees, -30 degrees ). In addition, REDOR experiments indicate that the torsion angles of the two C-terminal Ala residues, Ala(23) and Ala(24), are (phi, psi) = (-66 degrees, -22 degrees ) and those of N-terminal two Ala residues, Ala(13) and Ala(14) are (phi, psi) = (-70 degrees, -30 degrees ). Thus, the local structure of N-terminal and C-terminal residues, and also the neighboring residues of alpha-helical poly-Ala chain in the model peptide is a more strongly wound structure than found in typical alpha-helix structures.     

The strength with which a peptide group can form a hydrogen bond varies with the internal conformation of the polypeptide chain

The strength of the H-bond formed between a dipeptide and a proton acceptor molecule is assessed by correlated ab initio quantum calculations for a broad range of different conformations of the dipeptide. The H-bond energy is very sensitive to the internal (phi,psi) angles, even when the geometry of the H-bond does not vary significantly from one conformation to another. This result indicates that the peptide NH is a much less potent proton donor in certain conformations than in others. In particular, extended conformations of a polypeptide are capable of only weak H-bonds. Thus, the interstrand NH...O H-bonds in parallel and antiparallel beta-sheets are expected to be significantly weaker than those found in other conformations, such as helices, ribbons, and beta-bends, even if the H-bond geometries are similar.     

A conformational dynamics study of alpha-l-Rhap-(1-->2)[alpha-l-Rhap-(1-->3)]-alpha-l-Rhap-OMe in solution by NMR experiments and molecular simulations

The conformational preference of alpha-l-Rhap-(1-->2)[alpha-l-Rhap-(1-->3)]-alpha-l-Rhap-OMe in solution has been studied by NMR spectroscopy using one-dimensional (1)H,(1)H T-ROESY experiments and measurement of trans-glycosidic (3)J(C,H) coupling constants. Molecular dynamics (MD) simulations with a CHARMM22 type of force field modified for carbohydrates were performed with water as the explicit solvent. The homonuclear cross-relaxation rates, interpreted as effective proton-proton distances, were compared to those obtained from simulation. Via a Karplus torsional relationship, (3)J(C,H) values were calculated from simulation and compared to experimental data. Good agreement was observed between experimental data and the MD simulation, except for one inter-residue T-ROE between protons in the terminal sugar residues. The results show that the trisaccharide exhibits substantial conformational flexibility, in particular along the psi glycosidic torsion angles. Notably, for these torsions, a high degree of correlation (77%) was observed in the MD simulation revealing either psi(2)(+) psi(3)(+) or psi(2)(-)psi(3)(-) states. The simulations also showed that non-exoanomeric conformations were present at the phi torsion angles, but to a limited extent, with the phi(3) state populated to a larger extent than the phi(2) state. Further NMR analysis of the trisaccharide by translational diffusion measurements and (13)C T(1) relaxation experiments quantified global reorientation using an anisotropic model together with interpretation of the internal dynamics via the "model-free" approach. Fitting of the dynamically averaged states to experimental data showed that the psi(2)(+)psi(3)(+) state is present to approximately 49%, psi(2)(-) psi(3)(-) to approximately 39%, and phi(3) (non-exo) to approximately 12%. Finally, using a dynamic and population-averaged model, (1)H,(1)H T-ROE buildup curves were calculated using a full relaxation matrix approach and were found to be in excellent agreement with experimental data, in particular for the above inter-residue proton-proton interaction between the terminal residues.     

Structure distribution in an elastin-mimetic peptide (VPGVG)3 investigated by solid-state NMR

Elastin is an extracellular-matrix protein that imparts elasticity to tissues. We have used solid-state NMR to determine a number of distances and torsion angles in an elastin-mimetic peptide, (VPGVG)3, to understand the structural basis of elasticity. C-H and C-N distances between the V6 carbonyl and the V9 amide segment were measured using 13C-15N and 13C-1H rotational-echo double-resonance experiments. The results indicate the coexistence of two types of intramolecular distances: a third of the molecules have short C-H and C-N distances of 3.3 +/- 0.2 and 4.3 +/- 0.2 A, respectively, while the rest have longer distances of about 7 A. Complementing the distance constraints, we measured the (phi, psi ) torsion angles of the central pentameric unit using dipolar correlation NMR. The -angles of P7 and G8 are predominantly ~150, thus restricting the majority of the peptide to be extended. Combining all torsion angles measured for the five residues, the G8 C chemical shift, and the V6-V9 distances, we obtained a bimodal structure distribution for the PG residues in VPGVG. The minor form is a compact structure with a V6-V9 C=O-HN hydrogen bond and can be either a type II -turn or a previously unidentified turn with Pro (phi = -70, psi= 20 +/- 20) and Gly ( phi= -100 +/- 20, psi = -20 +/- 20). The major form is an extended and distorted beta-strand without a V6-V9 hydrogen bond and differs from the ideal parallel and antiparallel beta-strands. The other three residues in the VPGVG unit mainly adopt antiparallel beta-sheet torsion angles. Since (VPGVG)3 has the same 13C and 15N isotropic and anisotropic chemical shifts as the elastin-mimetic protein (VPGXG)n (X = V and K, n = 195), the observed conformational distribution around Pro and Gly sheds light on the molecular mechanism of elastin elasticity.     

Collagen stability: insights from NMR spectroscopic and hybrid density functional computational investigations of the effect of electronegative substituents on prolyl ring conformations

Collagen-like peptides of the type (Pro-Pro-Gly)(10) fold into stable triple helices. An electron-withdrawing substituent at the H(gamma)(3) ring position of the second proline residue stabilizes these triple helices. The aim of this study was to reveal the structural and energetic origins of this effect. The approach was to obtain experimental NMR data on model systems and to use these results to validate computational chemical analyses of these systems. The most striking effects of an electron-withdrawing substituent are on the ring pucker of the substituted proline (Pro(i)) and on the trans/cis ratio of the Xaa(i-1)-Pro(i) peptide bond. NMR experiments demonstrated that N-acetylproline methyl ester (AcProOMe) exists in both the C(gamma)-endo and C(gamma)-exo conformations (with the endo conformation slightly preferred), N-acetyl-4(R)-fluoroproline methyl ester (Ac-4R-FlpOMe) exists almost exclusively in the C(gamma)-exo conformation, and N-acetyl-4(S)-fluoroproline methyl ester (Ac-4S-FlpOMe) exists almost exclusively in the C(gamma)-endo conformation. In dioxane, the K(trans/cis) values for AcProOMe, Ac-4R-FlpOMe, and Ac-4S-FlpOMe are 3.0, 4.0, and 1.2, respectively. Density functional theory (DFT) calculations with the (hybrid) B3LYP method were in good agreement with the experimental data. Computational analysis with the natural bond orbital (NBO) paradigm shows that the pucker preference of the substituted prolyl ring is due to the gauche effect. The backbone torsional angles, phi and psi, were shown to correlate with ring pucker, which in turn correlates with the known phi and psi angles in collagen-like peptides. The difference in K(trans/cis) between AcProOMe and Ac-4R-FlpOMe is due to an n-->pi interaction associated with the Bürg-Dunitz trajectory. The decrease in K(trans/cis) for Ac-4S-FlpOMe can be explained by destabilization of the trans isomer because of unfavorable electronic and steric interactions. Analysis of the results herein along with the structures of collagen-like peptides has led to a theory that links collagen stability to the interplay between the pyrrolidine ring pucker, phi and psi torsional angles, and peptide bond trans/cis ratio of substituted proline residues.     

Flexible docking simulations: Scaled collective variable Monte Carlo minimization approach using Bezier splines,and comparison with a standard Monte Carlo algorithm

An algorithm for docking a flexible ligand onto a flexible or rigid receptor, using the scaled‐collective‐variables Monte Carlo with energy minimization approach, is presented. Energy minimization is shown to be one of the best techniques for distinguishing between native‐ and nonnative‐generated conformations. Incorporation of this technique into a Monte Carlo procedure enables one to distinguish the native conformation directly during the conformational search. It avoids the generation of a large number of ligand conformers for which more sophisticated energy evaluation tools would have had to be applied to identify the nativelike conformations. The efficiency of the Monte Carlo minimization was greatly improved by incorporating a new grid‐based energy evaluation technique using Bezier splines for which the energy function, as well as all of its derivatives, can be deduced from the values at the grid points. Comparison between our ECEPP/3‐based algorithm and the Monte Carlo algorithm presented elsewhere (Hart, T. N.; Read, R. J. Prot Struct Funct Genet 1992, 13, 206–222) has been made for docking NH₂ D Phe Pro Arg COOH, the noncovalent analog of NH₂ D Phe Pro Arg chloromethylketone (PPACK), onto the active site of human α‐thrombin. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 244–252, 1999     

Conformational preferences and cis-trans isomerization of L-lactic acid residue

The conformational study on N-acetyl- N'-methylamide of l-lactic acid (Ac-Lac-NHMe, the Lac dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore its backbone conformational preferences and cis-trans isomerization for the depsipeptide with an ester bond in the gas phase and in solution. In the gas phase and in chloroform, the conformation tB with a trans depsipeptide bond is most preferred for the Lac dipeptide, whose backbone torsion angles are phi approximately -150 degrees and psi approximately -5 degrees , juxtaposed to those of the 3 10-helical structure. The larger shift in phi is brought to reduce the repulsion between the two carbonyl carbons of the acetyl and NHMe groups. However, the polyproline II-like tF conformation becomes more populated and the relative stability of conformation tB decreases significantly as the solvent polarity increases. This may be ascribed to weakening a C(5) hydrogen bond between the depsipeptidyl oxygen and the carboxyl amide hydrogen that plays a role in stabilizing the conformation tB in the gas phase and in chloroform. The cis populations about the depsipeptide bond are nearly negligible in the gas phase and in solution. The rotational barriers to the cis-trans isomerization of the depsipeptide bond for the Lac dipeptide are calculated to be about 11 kcal/mol, which is about half of those for the Ala dipeptide, although they increase somewhat with the increase of solvent polarity. The cis-trans isomerization of the depsipeptide bond proceeds through either clockwise or anticlockwise rotations with torsion angles of about +90 degrees or -90 degrees , respectively, in the gas phase and in solution, whereas it has been known that the isomerization proceeds through only the clockwise rotation for alanyl and prolyl peptide bonds. The pertinent distances between the depsipeptidyl oxygen and the carboxyl amide hydrogen can describe the role of this hydrogen bond in stabilizing the transition state structures in the gas phase and in solution.     

Sampling conformational hyperspace: Techniques for improving completeness

Summary Three new strategies for sampling the conformation space accessible to a series of structurally diverse, flexible molecules are defined and compared to samples obtained using a fixed-grid torsion angle sampling strategy. A set of 28 potent inhibitors of angiotensin converting enzyme selected by Mayer et al. [J. Comput.-Aided Mol. Design, 1 (1987) 3] and the unrestricted active-site model proposed by Waller et al. [to be published] are used to produce a realistic experimental setting. We modified our Constrained Search algorithm [Dammkoehler et al., J. Comput.-Aided Mol. Design, 3 (1989) 3] to support these new sampling strategies, performing a series of 64 simulations (search experiments) and generating a large set of sterically allowed conformations. In each experiment, we systematically vary the internal torsion angles in each molecule using one of the sampling strategies. The common orientations of preselected functional groups thought to represent those dominating the interaction with the enzyme and presented by the set of molecules are classified and recorded for each experiment. Pairwise distances between groups are used to characterize the geometry of the common orientations. The results of each experiment, represented by a set of distance values, are compared and combined to evaluate the completeness of the conformational sampling. While no pure strategy or single search experiment was found to be adequate to fully explore the set of common sterically allowed conformations, a new sampling technique, called adaptive radial sampling, is shown to be significantly more complete than the commonly used fixed grid sampling.     

Free energy surfaces for the alpha(1 --> 4)-glycosidic linkage: implications for polysaccharide solution structure and dynamics

We present a potential of mean force surface for rotation about phi and psi dihedral angles of the alpha(1 --> 4)-glycosidic linkage in the maltose disaccharide (4-O-alpha-d-glucopyranosyl-d-glucopyranose) in aqueous solution. Comparison of the vacuum and solution free energy surfaces for maltose shows the principal effects of water to be an increase in the rotational freedom of the alpha(1 --> 4) linkage brought about by lowering the energy barrier for syn to anti conformational changes as well as expansion of the range of low-energy phi,psi conformations. This free energy analysis thus provides a thermodynamic and conformational rationale for the effects of water on alpha(1 --> 4)-linked polysaccharides and carbohydrate glasses.     

Flexibility of "polyunsaturated fatty acid chains" and peptide backbones: A comparative ab initio study

The conformational properties of omega-3 type of polyunsaturated fatty acid (PUFA) chains and their fragments were studied using Hartree-Fock (RHF/3-21G) and DFT (B3LYP/6-31G(d)) methods. Comparisons between a unit (U) fragment of the PUFA chain and a mono N-Ac-glycine-NHMe residue show that both structures have the same sequence of sp2-sp3-sp2 atoms. The flexibility of PUFA originates in the internal rotation about the above pairs of sigma bonds. Therefore, potential energy surfaces (PESs) were generated by a scan around the terminal dihedral angles (phi t1 and phi t2) as well as the phi 1 and psi 1 dihedrals of both 1U congeners (Me-CHCH-CH2-CHCHMe and MeCONH-CH2-CONHMe) at the RHF/3-21G level of theory. An interesting similarity was found in the flexibility between the cis allylic structure and the trans peptide models. A flat landscape can be seen in the cis 1U (hepta-2,5-diene) surface, implying that several conformations are expected to be found in this (PES). An exhaustive search carried out on the 1U and 2U models revealed that straight chain structures such as trans and cis beta (phi 1 approximately psi 1 approximately 120 degrees; phi 2 approximately psi 2 approximately -120 degrees) or trans and cis extended (phi 1 approximately psi 1 approximately phi 2 approximately psi 2 approximately 120 degrees) can be formed at the lowest energy of both isomers. However, forming helical structures, such as trans helix (phi 1 approximately -120 degrees, psi 1 approximately 12 degrees; phi 2 approximately -120 degrees, psi 2 approximately 12 degrees) or cis helix (phi 1 approximately -130 degrees, psi 1 approximately 90 degrees; phi 2 approximately -145 degrees, psi 2 approximately 90 degrees) will require more energy. These six conformations, found in 2U, were selected to construct longer chains such as 3U, 4U, 5U, and 6U to obtain the thermochemistry of secondary structures. The variation in the extension or compression of the chain length turned out to be a factor of 2 between the helical and nonhelical structures. The inside diameter of the "tube" of cis helix turned out to be 3.5 A after discounting the internal H atoms. Thermodynamic functions were computed at the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d). The cis-trans isomerization energy of 1.7 +/- 0.2 kcal mol(-1) unit(-1) for all structure pairs indicates that the conformer selection was consistent. A folding energy of 0.5 +/- 0.1 kcal mol(-1) unit(-1) has been extracted from the energy comparison of the helices and most extended nonhelical structures. The entropy change associated with the folding (Delta S(folding)) is decreases faster with the degree of polymerization (n) for the cis than for the trans isomer. As a consequence, the linear relationships between (Delta G(folding)) and n for the cis and trans isomer crossed at about n = 3. This suggested that the naturally occurring cis isomer less ready to fold than the trans isomer since a greater degree of organization is exhibited by the cis isomer during the folding process. The result of this work leads to the question within the group additivity rule: could the method applied in our study of the folding of polyallylic hydrocarbons be useful in investigating the thermochemistry of protein folding?     

Symbolic representation of the molecular conformation of calixarenes

In calixarene chemistry there is a continuous search for new shaping units or substructures useful for molecular recognition or for the binding of ions. The problem of assigning their molecular conformations cannot be dealt with by the use of the dihedral angles as done until now, because this method contains intrinsic ambiguities. The new approach, proposed here, is based on the use of the set ofn pairs of torsion angles (conformational parameters) which involve the flexible part of the calixarene and it is free of ambiguities. Moreover, knowledge of the set of conformational parameters allows one to build straightforwardly three-dimensional molecular models. A symbolic representation of the molecular conformation of any calix[n]arene may be obtained by combining the Schöenflies symbol of the molecular symmetry together with the signs of the conformational parameters.     

简化的系统搜索法及其在构象分析中的应用

多肽的构象研究除了可以用X-射线晶体学及二维核磁共振等实验方法外,理论计算的方法有系统搜索法、蒙特卡洛方法、距离几何方法、分子动力学方法及能量极小化等.系统搜索法具有构象空间搜索彻底的特点,相对来说找到系统整体极小值的可能性较大,但由于其计算量较大,对于多肽及蛋白质很难实现.我们对系统搜索法进行了简化,不是同时旋转所有的二面角,而是成对地进行,以迭代的方法达到收敛,最后得到可能的构象.     

Determination of peptide backbone torsion angles using double-quantum dipolar recoupling solid-state NMR spectroscopy

Several approaches for utilizing dipolar recoupling solid-state NMR (ssNMR) techniques to determine local structure at high resolution in peptides and proteins have been developed. However, many of these techniques measure only one torsion angle or are accurate for only certain classes of secondary structure. Additionally, the efficiency with which these dipolar recoupling experiments suppress the deleterious effects of chemical shift anisotropy (CSA) at high magnetic field strengths varies. Dipolar recoupling with a windowless sequence (DRAWS) has proven to be an effective pulse sequence for exciting double-quantum (DQ) coherences between adjacent carbonyl carbons along the peptide backbone. By allowing this DQ coherence to evolve, it is possible to measure the relative orientations of the CSA tensors and subsequently use this information to determine the Ramachandran torsion angles phi and psi. Here, we explore the accuracies of the assumptions made in interpreting DQ-DRAWS data and demonstrate their fidelity in measuring torsion angles corresponding to a variety of secondary structures irrespective of hydrogen-bonding patterns. It is shown how a simple choice of isotopic labels and experimental conditions allows accurate measurement of backbone secondary structures without any prior knowledge. This approach is considerably more sensitive for determining structure in helices and has comparable accuracy for beta-sheet and extended conformations relative to other methods. We also illustrate the ability of DQ-DRAWS to distinguish between structures in heterogeneous samples.     

Ramachandran-type plots for glycosidic linkages: Examples from molecular dynamic simulations using the Glycam06 force field

The goals of this article are to (1) provide further validation of the Glycam06 force field, specifically for its use in implicit solvent molecular dynamic (MD) simulations, and (2) to present the extension of G.N. Ramachandran's idea of plotting amino acid phi and psi angles to the glycosidic phi, psi, and omega angles formed between carbohydrates. As in traditional Ramachandran plots, these carbohydrate Ramachandran-type (carb-Rama) plots reveal the coupling between the glycosidic angles by displaying the allowed and disallowed conformational space. Considering two-bond glycosidic linkages, there are 18 possible conformational regions that can be defined by (alpha, phi, psi) and (beta, phi, psi), whereas for three-bond linkages, there are 54 possible regions that can be defined by (alpha, phi, psi, omega) and (beta, phi, psi, omega). Illustrating these ideas are molecular dynamic simulations on an implicitly hydrated oligosaccharide (700 ns) and its eight constituent disaccharides (50 ns/disaccharide). For each linkage, we compare and contrast the oligosaccharide and respective disaccharide carb-Rama plots, validate the simulations and the Glycam06 force field through comparison to experimental data, and discuss the general trends observed in the plots.     

Steric trigger as a mechanism for CB1 cannabinoid receptor activation

To determine the moiety that behaves as the steric trigger to activate the CB(1) cannabinoid receptor, conformational properties of the nonclassical cannabinoid CP55244, one of the most potent CB(1) receptor agonists, were characterized by conformational analysis, rotational barrier calculations, and molecular dynamics (MD) simulations. It was shown from the present MD simulations that the torsion angles phi1 and phi4 of the C3 side chain showed the most dramatic change when compared with the ground-state receptor-bound conformation, indicating that rotation around these torsion angles is responsible for releasing the ligand strain energy. Multiple stages would be involved in the ligand conformational change. As a molecular mechanism for the ligand-induced CB(1) receptor conformational change, we propose that the C3 side chain serves as the steric trigger, while the ACD-ring moiety of CP55244 serves as the plug. Steric clash with helices within the binding pocket would induce microconformational adaptation within the protein. This mechanism would suggest that rotational flexibility in a ligand may be as important a determinant of agonist activity as the pharmacophoric elements that can be identified.     

Experimental evidence for the existence of non-exo-anomeric conformations in branched oligosaccharides: NMR analysis of the structure and dynamics of aminoglycosides of the neomycin family

It is commonly known that the exo-anomeric effect is a major factor governing the conformational behavior of naturally occurring oligosaccharides. Conformational flexibility in these molecules mainly concerns the aglycon psi angle since phi is restricted by this stereo-electronic effect. In fact, to the best of our knowledge no case of a natural glycoside adopting a non-exo-anomeric conformation in solution has yet been reported. With respect to the flexibility among naturally occurring carbohydrates, branched type oligosaccharides including sugar residues glycosidated at contiguous positions (such as blood type carbohydrate antigens Lewis X) have been considered as the paradigm of rigid saccharides--the rigidity being enhanced by van der Waals interactions. Herein, we demonstrate unambiguously that both common beliefs are not to be generalized. For example in neomycin B, a branched oligosaccharide antibiotic, a large number of non-exo-anomeric conformations was detected in solution for the first time in naturally occurring sugars. This unusual behavior is attributed to branching. Here, polar contacts between non-vicinal sugar units lead to an enhanced flexibility of the ribose glycosidic torsion phi. The influence of sugar flexibility on RNA recognition will also be discussed.