Low Mode Search. An Efficient, Automated Computational Method for Conformational Analysis:  Application to Cyclic and Acyclic Alkanes and Cyclic Peptides

Dietrich, Michael; Heınze, Jürgen; Krieger, Claus; Neugebauer, Franz A.

doi:10.1021/ja952478m

Cited by 412 publications

(359 citation statements)

References 61 publications

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“…After the Monte Carlo run, an additional 3000 steps were performed with the low-mode (LMOD) conformational searching technique. 30 From the results of the search, several low-energy conformers were selected as starting geometries for density functional calculations.…”

Section: Methodsmentioning

confidence: 99%

Structures of Protonated Arginine Dimer and Bradykinin Investigated by Density Functional Theory: Further Support for Stable Gas-Phase Salt Bridges

Strittmatter

Williams

2000

J. Phys. Chem. A

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The gas-phase structures and energetics of both protonated arginine dimer and protonated bradykinin were investigated using a combination of molecular mechanics with conformational searching to identify candidate low-energy structures, and density functional theory for subsequent minimization and energy calculations. For protonated arginine dimer, a good correlation (R = 0.88) was obtained between the molecular mechanics and EDF1 6-31+G* energies, indicating that mechanics with MMFF is suitable for finding low-energy conformers. For this ion, the salt-bridge or ion-zwitterion form was found to be 5.7 and 7.2 kcal/mol more stable than the simple protonated or ion-molecule form at the EDF1 6-31++G** and B3LYP 6-311++G** levels. For bradykinin, the correlation between the molecular mechanics and DFT energies was poor (R = 0.28), indicating that many lowenergy structures are likely passed over in the mechanics conformational searching. This result suggests that structures of this larger peptide ion obtained using mechanics calculations alone are not necessarily reliable. The lowest energy structure of the salt-bridge form of bradykinin is 10.6 kcal/mol lower in energy (EDF1) than the lowest energy simple protonated form at the 6-311G* level. Similarly, the average energy of all salt-bridge structures investigated is 13.6 kcal/mol lower than the average of all the protonated forms investigated. To the extent that a sufficient number of structures are investigated, these results provide some additional support for the salt-bridge form of bradykinin in the gas phase.

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Section: Methodsmentioning

confidence: 99%

Structures of Protonated Arginine Dimer and Bradykinin Investigated by Density Functional Theory: Further Support for Stable Gas-Phase Salt Bridges

Strittmatter

Williams

2000

J. Phys. Chem. A

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“…Due to the greater flexibility of the cocaine molecule, the CSP method was adapted to include an automated conformer search: conformations were generated using the low-mode search method 54 and the all-atom optimized potentials for liquid simulations (OPLS-aa) force field 55 . The most stable resulting conformations were refined using constrained B3LYP/6-31G(d,p) geometry optimisations and 16 starting conformations were selected for crystal structure generation.…”

Section: C Crystal Structure Predictionmentioning

confidence: 99%

Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy

Baias

Widdifield

Dumez

et al. 2013

Phys. Chem. Chem. Phys.

164

251

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A protocol for the ab initio crystal structure determination of powdered solids at natural isotopic abundance by combining solid-state NMR spectroscopy, crystal structure prediction, and DFT chemical shift calculations was evaluated to determine the crystal structures of four small drug molecules: cocaine, flutamide, flufenamic acid, and theophylline. For cocaine, flutamide and flufenamic acid, we find that the assigned 1 H isotropic chemical shifts provide sufficient discrimination to determine the correct structures from a set of predicted structures using the root-mean-square deviation (rmsd) between experimentally determined and calculated chemical shifts. In most cases unassigned shifts could not be used to determine the structures. This method requires no prior knowledge of the crystal structure, and was used to determine the correct crystal structure to within an atomic rmsd of less than 0.12 Å with respect to the known reference structure. For theophylline, the NMR spectra are too simple to allow for unambiguous structure selection.

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“…Molecular Modeling The energy-minimum structures under three environmental conditions (gas-phase, in CHCl 3 , and in water) were obtained by conformation searches with pure LowMode methods 27) and subsequent multiple-minimization. All the calculations were done with the OPLS-AA force field.…”

Section: Methodsmentioning

confidence: 99%

Anchoring Cationic Amphiphiles for Nucleotide Delivery Significance of DNA Release from Cationic Liposomes for Transfection

Hirashima

Minatani

Hattori

et al. 2007

Biological & Pharmaceutical Bulletin

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Establishment of an efficient and safe method for introducing exogenous nucleotides into mammalian cells is critical for both basic sciences and clinical applications, such as gene therapy.1) Among various methods for gene transfection, lipofection using cationic liposomes is considered to be a promising way to deliver a foreign gene to target cells. [2][3][4] Although many kinds of cationic liposomes have been developed for lipofection, [5][6][7][8][9][10] further studies are still required to achieve a transfection efficiency comparable with that of viral vectors. The results of a recent structural study indicated that a multilamellar or inverted hexagonal structure with alternating lipid bilayer and DNA monolayer might be favorable.11-13) Therefore, the structure of the lipid bilayers of cationic liposomes are probably conserved upon complexation with DNA. The width of the bilayer is estimated to be 36 Å.11-13) Recently, we have developed several cationic amphiphiles for nucleotide delivery.14,15) These are lithocholic acid-based molecules (see Chart 1) which bear cis-decalin structures, while the frequently used cholestane-based molecules (such as DC-Chol) have trans-decalin structures. The additional hydrophobic region at the 3-hydroxyl group of lithocholic acid derivatives may enforce hydrophobic interaction in the assembly, resulting in anchoring of the amphiphiles to the bilayer. We found that the hydrophobic appendant at the 3-position and the orientation and extension of the hydrophobic regions around the ether linkage both significantly influence the gene transfection. However, the mechanism of the dependence of the transfection efficiency on molecular structure was not elucidated. In liposome-mediated transfection, a liposome-DNA complex is taken into target cells by endocytosis. [16][17][18][19][20] The internalized exogenous DNA is released by disruptive interaction between liposomal membrane and endosomal membrane. [21][22][23][24][25] The released DNA in the cytoplasm is translocated into the nucleus, while DNA remaining in the endosomes is degraded in lysosomes. Therefore, the efficiency of cellular uptake of the liposome-DNA complex and the efficiency of release of DNA from both the endosomes and the liposomes are postulated to be major factors that determine the transfection efficiency, which can be estimated by means of luciferase assay. In the present study, we prepared cationic liposomes from lithocholic acid-polyamine conjugates (Chart 1), and investigated two chemico-physical characteristics that may affect the efficiency of the processes mentioned above. Firstly, we examined the encapsulation of DNA and compaction of the liposome-DNA complex, since the liposome-DNA interaction is thought to facilitate the uptake of liposome-DNA complexes by target cells and also to protect the plasmid DNA from enzymatic degradation. Secondly, we examined the ability of cationic liposomes to release DNA upon membrane fusion with anionic liposomes, which mimic the endosomal membrane. [21][22][23][24][25] T...

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Low Mode Search. An Efficient, Automated Computational Method for Conformational Analysis: Application to Cyclic and Acyclic Alkanes and Cyclic Peptides

Cited by 412 publications

References 61 publications

Structures of Protonated Arginine Dimer and Bradykinin Investigated by Density Functional Theory: Further Support for Stable Gas-Phase Salt Bridges

Structures of Protonated Arginine Dimer and Bradykinin Investigated by Density Functional Theory: Further Support for Stable Gas-Phase Salt Bridges

Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy

Anchoring Cationic Amphiphiles for Nucleotide Delivery Significance of DNA Release from Cationic Liposomes for Transfection

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