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At least 397 records · Page 22Linked to original sources
PubMed1997

Homology modeling using simulated annealing of restrained molecular dynamics and conformational search calculations with CONGEN: application in predicting the three-dimensional structure of murine homeodomain Msx-1.

We have developed an automatic approach for homology modeling using restrained molecular dynamics and simulated annealing procedures, together with conformational search algorithms available in the molecular mechanics program CONGEN (Bruccoleri RE, Karplus M, 1987, Biopolymers 26:137-168). The accuracy of the method is validated by "predicting" structures of two homeodomain proteins with known three-dimensional structures, and then applied to predict the three-dimensional structure of the homeodomain of the murine Msx-1 transcription factor. Regions of the unknown protein structure that are highly homologous to the known template structure are constrained by "homology distance constraints," whereas the conformations of nonhomologous regions of the unknown protein are defined only by the potential energy function. A full energy function (excluding explicit solvent) is employed to ensure that the calculated structures have good conformational energies and are physically reasonable. As in NMR structure determinations, information on the consistency of the structure prediction is obtained by superposition of the resulting family of protein structures. In this paper, our homology modeling algorithm is described and compared with related homology modeling methods using spatial constraints derived from the structures of homologous proteins. The software is then used to predict the DNA-bound structures of three homeodomain proteins from the X-ray crystal structure of the engrailed homeodomain protein (Kissinger CR et al., 1990, Cell 63:579-590). The resulting backbone and side-chain conformations of the modeled yeast Mat alpha 2 and D. melanogaster Antennapedia homeodomains are excellent matches to the corresponding published X-ray crystal (Wolberger C et al., 1991, Cell 67:517-528) and NMR (Billeter M et al., 1993, J Mol Biol 234:1084-1097) structures, respectively. Examination of these structures of Msx-1 reveals a network of highly conserved surface salt bridges that are proposed to play a role in regulating protein-protein interactions of homeodomains in transcription complexes.

Algorithms↗
PubMed2006

Conformational states and dynamics of rhodopsin in micelles and bilayers.

Nitroxide sensors were placed in rhodopsin at sites 140, 227, 250, and 316 to monitor the dynamics and conformation of the receptor at the cytoplasmic surface in solutions of dodecyl maltoside (DM), digitonin, and phospholipid bilayers of two compositions. The EPR spectra reveal a remarkable similarity of rhodopsin structure and the activating conformational change in DM and bilayers, the hallmark of which is an outward tilt of transmembrane helix VI. This conformational change is blocked in solutions of digitonin, although changes in optical absorbance accompany activation, showing that absorbance and structural changes are not necessarily coupled. In DM and bilayers, the receptor is apparently in equilibrium between conformational substates whose populations are modulated by activation. Despite the general similarity in the two environments, the receptor conformations have increased flexibility in DM relative to bilayers. For the activated receptor in DM and bilayers, a pH-dependent conformational equilibrium is identified that may correspond to the optically characterized MII(a)()-MII(b)() equilibrium. No specific effects of headgroup composition on receptor conformation in lipid bilayers were found.

Amino Acid Substitution↗
PubMed2005

Conformation analyses, dynamic behavior, and amide bond distortions of medium-sized heterocycles. 2. Partially and fully reduced 1-benzazocines, benzazonines, and benzazecines.

Partially and fully reduced forms of benzo-fused eight- to ten-membered nitrogen heterocycles (1-benzazecines, 1-benzazonines and 1-benzazecines) have been prepared. Conformational features, transannular distances and dynamic behavior were studied using X-ray crystallography and VT NMR spectroscopy. The amide moiety in the nine-membered benzazonine ring 5b favors N-pyramidization, whereas the ten-membered benzazecine 5c adopts an amide twist. Molecular mechanics calculations reveals a correlation between the amide twist (tau) and ring stability. The dynamic behavior of the heterocycles in solution were also found to be dependent on the extent and nature of the amide distortion. We thus conclude that ring strain of these medium-sized heterocyclic rings is relieved through amide distortion, which leads to a more stable structure.

Amides↗
PubMed1988

Importance of folded monomer and extended antiparallel dimer structures as enkephalin active conformation. Molecular dynamics simulations of [Met5]enkephalin in water.

Simulations of the molecular dynamics of the [Met5]enkephalin monomer and dimer structures in water have been carried out. The dynamic trajectories have been analyzed in terms of the distances between intra- or intermolecular polar atoms. The time-correlated conformational transitions of an extended monomer structure have been converged into a stationary state among the beta-bend folded forms. However, the dynamics simulation of an extended antiparallel dimer structure has shown no noticeable conformation change. These results imply that both the beta-bend monomer and the extended dimer structures exist together as the fundamental conformation of enkephalins.

Calorimetry↗
PubMed2005

Loop conformation and dynamics of the Escherichia coli HPPK apo-enzyme and its binary complex with MgATP.

Comparison of the crystallographic and NMR structures of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) suggests that the enzyme may undergo significant conformational change upon binding to its first substrate, ATP. Two of the three surface loops (loop 2 and loop 3) accounting for most of the conformational differences appear to be confined by crystal contacts, raising questions about the putative large-scale induced-fit conformational change of HPPK and the functional roles of the conserved side-chain residues on the loops. To investigate the loop dynamics in crystal-free environment, we carried out molecular dynamics and locally enhanced sampling simulations of the apo-enzyme and the HPPK.MgATP complex. Our simulations showed that the crystallographic B-factors underestimated the loop dynamics considerably. We found that the open-conformation of loop 3 in the binary complex is accessible to the apo-enzyme and is the favored conformation in solution phase. These results revise our previous view of HPPK-substrate interactions and the associated functional mechanism of conformational change. The lessons learned here offer valuable structural insights into the workings of HPPK and should be useful for structure-based drug design.

Adenosine Triphosphate↗
PubMed1988

Preferred conformation and dynamics of the glycerol backbone in phospholipids. An NMR and X-ray single-crystal analysis.

The conformation of the glycerol group of a number of diacyl and monoacyl (lyso) phospholipids differing in the chemical nature of the head group was studied by 1H high-resolution NMR and X-ray crystallography. The NMR measurements were carried out with solutions or micellar dispersions of the lipids in deuteriated organic solvents or 2H2O. Both solutions, in which the lipid is present as monomers, and lipid micelles give rise to good high-resolution NMR spectra exhibiting spin coupling hyperfine interactions. From 1H spin coupling it is concluded that there are two stable conformations about the glycerol C(2)-C(3) bond of phospholipids. One of these (rotamer A) is characterized by torsion angles theta 3 = antiperiplanar, theta 4 = +synclinal, and the other (rotamer B) by theta 3 = +synclinal, theta 4 = -synclinal. In both rotamers A and B the ester oxygens on the glycerol carbon atoms C(2) and C(3) are synclinal, and hence both types of rotamers readily allow the parallel alignment of the two hydrocarbon chains. By comparison of NMR and single-crystal X-ray data it is obvious that both conformations are minimum free energy conformations. Rotamer A is the conformation prevailing in phospholipid single-crystal structures. The conformation of rotamer B is also found in phospholipid single-crystal structures though to a lesser extent, e.g., in 2,3-dilauroyl-DL-glycero-1-phospho-N,N-dimethylethanolamine and 2,3-dimyristoyl-D-glycero-phospho-DL-glycerol. NMR measurements indicate that in liquid crystals the diacylglycerol part of phospholipids fluctuates between the two stable staggered conformations of rotamers A and B.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycerol↗
PubMed1989

Didemnin B. Conformation and dynamics of an antitumour and antiviral depsipeptide studied in solution by 1H and 13C. n.m.r. spectroscopy.

The solution conformation of didemnin B, the most potent member of a family of depsipeptides that shows antitumour, antiviral, and immunosuppressive activity, has been studied in chloroform solution using n.m.r. spectroscopy. 1H and 13C spectra have been assigned from analysis of a number of two-dimensional homonuclear and heteronuclear chemical shift correlation experiments which confirm the recently corrected primary structure of the molecule. The conformation of the peptide has been deduced from measurements of the temperature dependence of the NH chemical shifts, analysis of coupling constant data and primarily through NOE effects observed in the rotating frame. Interproton distance bounds determined from a quantitative analysis of the ROE data provide 41 constraints from which a family of closely related structures were calculated using distance geometry algorithms. A type II beta-turn involving residues Thr6, Leu7, and Pro8 is well represented in the computed conformers as is a hydrogen bonding interaction between the NH of Leu3 and the carbonyl oxygen of Thr6. This latter interaction causes the linear portion of the structure to fold back over the depsipeptide ring, imparting to it a degree of structural stability as well as giving the molecule a somewhat globular character. Only one transannular hydrogen bond, between Ist1 NH and Leu3 carbonyl, stabilizes the conformation of the depsipeptide, which has an irregular non-planar configuration. The small temperature coefficients (less than 2.0 x 10(-3) ppm/degrees C) for the NHs of Ist1 and Leu3 are consistent with their involvement in these hydrogen bonding interactions. We find that many of the structural features observed in the crystalline form of didemnin B are conserved in solution. Analysis of the 13C spin-lattice relaxation rates of the protonated carbons reveals small variations in effective correlation times at specific sites in the molecule. The data suggests that the peptide segment encompassing residues Leu3 through to Thr6 is in a more motionally restricted part of the structure.

Amino Acid Sequence↗
PubMed2003

Dynamics of conformal maps for a class of non-Laplacian growth phenomena.

Time-dependent conformal maps are used to model a class of growth phenomena limited by coupled non-Laplacian transport processes, such as nonlinear diffusion, advection, and electromigration. Both continuous and stochastic dynamics are described by generalizing conformal-mapping techniques for viscous fingering and diffusion-limited aggregation, respectively. The theory is applied to simulations of advection-diffusion-limited aggregation in a background potential flow. A universal crossover in morphology is observed from diffusion-limited to advection-limited fractal patterns with an associated crossover in the growth rate, controlled by a time-dependent effective Péclet number. Remarkably, the fractal dimension is not affected by advection, in spite of dramatic increases in anisotropy and growth rate, due to the persistence of diffusion limitation at small scales.

Journal Article↗
PubMed2003

Impact of a micromultileaf collimator on stereotactic radiotherapy of uveal melanoma.

PURPOSE: To evaluate the impact of a micro multileaf collimator (mMLC) on Linac-based stereotactic radiotherapy (SRT) of uveal melanoma by comparing circular arc with static conformal, dynamic arc, and intensity-modulated SRT. MATERIALS AND METHODS: Forty uveal melanoma patients were selected from approximately 100 patients treated with SRT since 1996. For each patient, four treatment plans (BrainSCAN XL, V5.0) were made: conventional arc, static conformal, dynamic arc plan, and intensity-modulated radiotherapy (IMRT). The goal of treatment planning was to fully encompass the planning target volume (PTV) by the 80% isodose while minimizing doses to the optic nerve and lens. The following parameters were evaluated: target conformity; target homogeneity; ratio of the target volume and 50% isodose volume; normal tissue receiving doses >/=80%, >/=50%, and >/=20%; central nervous system volume irradiated to >/=20%; optical nerve volume irradiated >/=50%, D(max) of the lens; lens volume receiving >/=20%; and monitor units. RESULTS: PTVs ranged from 0.68 to 4.90 cm(3) (mean 1.97 +/- 0.97 cm(3)). The average reduction of the prescription isodose volume was 1-1.5 cm(3) for conformal (range 2.6-0.3 cm(3)), dynamic arc (range 2.5-0.3 cm(3)), and IMRT plans (range 3.9-0.1 cm(3)), compared with conventional arc therapy. Central nervous system volumes irradiated to doses >/=20% were smallest for conventional or dynamic arc treatments. Average target dose homogeneity values were 1.74 +/- 0.50 for arc, 1.27 +/- 0.02 for static mMLC, 1.26 +/- 0.01 for dynamic arc, and 1.15 +/- 0.03 for IMRT plans. IMRT helped to reduce doses to the lens but did not provide an advantage for optical nerve sparing. When applying IMRT, the monitor units increased by approximately one-third compared with static mMLC-based SRT. CONCLUSIONS: Conformal mMLC and dynamic arc SRT are the treatment options of choice for Linac-based SRT of uveal melanoma. They present dosimetric advantages, while being highly efficient in treatment planning and delivery.

Humans↗
PubMed1995

Conformation and dynamics of a cyclic (1-->2)-beta-D-glucan.

A molecular modelling and nuclear magnetic resonance spectroscopic study was performed in order to gain insight into the conformational preferences of cyclosophoroheptadecaose. MM3 molecular mechanics calculations predicted a non-symmetric conformer with a small cavity of 3.7 A diameter as the lowest energy form. Molecular dynamics simulations gave insight into the dynamics of the free cyclosophoroheptadecaose and also supported the results of molecular mechanics calculations. A fair agreement was found between experimental data and corresponding average values predicted by molecular modelling.

Carbohydrate Conformation↗
PubMed1996

The effect of hydration upon the conformation and dynamics of neocarrabiose, a repeat unit of beta-carrageenan.

Molecular mechanics calculations have been performed for the disaccharide neocarrabiose, one of the repeat units of beta-carrageenan, as a general model for the (1-->3)-linkage in the carrageenans. An adiabatic conformational energy map for this molecule has been prepared by constrained energy minimization and compared to previously reported relaxed maps. Neither the experimentally determined crystal structure of neocarrabiose nor the fiber diffraction conformation of iota-carrageenan is a low energy conformation on the relaxed Ramachandran map. Molecular dynamics simulations in vacuum produced trajectories consistent with this relaxed vacuum surface. However, a simulation with explicitly included solvent water molecules produced a trajectory that remained in the region of the two experimental structures. This dramatic solvation effect is apparently the result of the breaking of an interring hydrogen bond between the O2 hydroxyl groups of neocarrabiose as both groups hydrogen bond to solvent.

Carbohydrate Conformation↗
PubMed2002

Myoglobin-CO conformational substate dynamics: 2D vibrational echoes and MD simulations.

Two-dimensional (2D) infrared vibrational echoes were performed on horse heart carbonmonoxymyoglobin (MbCO) in water over a range of temperatures. The A(1) and A(3) conformational substates of MbCO are found to have different dephasing rates with different temperature dependences. A frequency-frequency correlation function derived from molecular dynamics simulations on MbCO at 298 K is used to calculate the vibrational echo decay. The calculated decay shows substantial agreement with the experimentally measured decays. The 2D vibrational echo probes protein dynamics and provides an observable that can be used to test structural assignments for the MbCO conformational substates.

Animals↗
PubMed2006

HIV-1 Tat is a natively unfolded protein: the solution conformation and dynamics of reduced HIV-1 Tat-(1-72) by NMR spectroscopy.

Tat (transactivator of transcription) is a small RNA-binding protein that plays a central role in the regulation of human immunodeficiency virus type 1 replication and in approaches to treating latently infected cells. Its interactions with a wide variety of both intracellular and extracellular molecules is well documented. A molecular understanding of the multitude of Tat activities requires a determination of its structure and interactions with cellular and viral partners. To increase the dispersion of NMR signals and permit dynamics analysis by multinuclear NMR spectroscopy, we have prepared uniformly 15N- and 15N/13C-labeled Tat-(1-72) protein. The cysteine-rich protein is unambiguously reduced at pH 4.1, and NMR chemical shifts and coupling constants suggest that it exists in a random coil conformation. Line broadening and multiple peaks in the Cys-rich and core regions suggest that transient folding occurs in two of the five sequence domains. NMR relaxation parameters were measured and analyzed by spectral density and Lipari-Szabo approaches, both confirming the lack of structure throughout the length of the molecule. The absence of a fixed conformation and the observation of fast dynamics are consistent with the ability of Tat protein to interact with a wide variety of proteins and nucleic acid and support the concept of a natively unfolded protein.

Computer Simulation↗
PubMed2005

Solution conformation and dynamics of the ion pairs originating from the reaction of B(C6F5)3 with bisindenyl dimethyl zirconium complexes.

The two ion pairs [(4,7-Me(2)indenyl)(2)ZrMe](+)[MeB(C(6)F(5))(3)](-) (1 b) and [(indenyl)(2)ZrMe](+) [MeB(C(6)F(5))(3)](-) (2 b) have been generated in situ by reaction of stoichiometric B(C(6)F(5))(3) with the corresponding dimethyl zirconocenes. It has been shown that molecular mechanics computations, guided by experimental (1)H/(1)H NOE correlations, can provide information on the conformers present in solution. The dynamics of the ion pairs has also been investigated, showing the occurrence of both the processes previously characterized for this class of compounds, namely the B(C(6)F(5))(3) migration between the two methyl groups and dissociation-recombination of the whole [MeB(C(6)F(5))(3)](-) anion, the latter process being much faster than the first one (about three order of magnitude). Moreover, it has been shown that in certain conditions intermolecular processes can occur, which mimic the above-mentioned dissociative exchanges. In particular, the presence of species containing loosely bound [MeB(C(6)F(5))(3)](-) anion fastens the exchange of this anion, while the presence of free B(C(6)F(5))(3) accelerates its exchange between the two methyl sites.

Algorithms↗
PubMed1991

Multi-conformational peptide dynamics derived from NMR data: a new search algorithm and its application to antamanide.

A search algorithm, called MEDUSA, is presented which allows the determination of multiple conformations of biomolecules in solution with exchange rate constants typically between 10(3) and 10(7) s-1 on the basis of experimental high-resolution NMR data. Multiples of structures are generated which are consistent as ensembles with NMR cross-relaxation rates (NOESY, ROESY), scalar J-coupling constants, and T1 rho measurements. The algorithm is applied to the cyclic decapeptide antamanide dissolved in chloroform. The characteristic radio-frequency field dependence of the T1 rho relaxation rates found for the NH protons of Val1 and Phe6 can be explained by a dynamical exchange between two structures.

Algorithms↗
PubMed2003

Conformations and dynamics of Ets-1 ETS domain-DNA complexes.

Molecular dynamics studies have been performed for 3.5 ns on the ETS domain of Ets-1 transcription factor bound to the 14-bp DNA, d(AGTGCCGGAAATGT), comprising the core sequence of high-affinity (GGAA), ETS-GGAA. In like manner, molecular dynamics simulations have been carried out for 3.9 ns on the mutant low-affinity core sequence, GGAG (ETS-GGAG). Analyses of the DNA backbone of ETS-GGAG show conformational interconversions from BI to BII substates. Also, crank shaft motions are noticed at the mutated nucleotide base pair step after 1500 ps of dynamics. The corresponding nucleotide of ETS-GGAA is characteristic of a BI conformation and no crank shaft motions are observed. The single mutation of ETS-GGAA to ETS-GGAG also results in variations of helical parameters and solvent-accessible surface area around the major and minor grooves of the DNA. The presence of water contacts during the entire simulation proximal to the fourth base pair step of core DNA sequence is a characteristic feature of ETS-GGAA. Such waters are more mobile in ETS-GGAG at 100 ps and distant after 1500 ps. Anticorrelated motions between certain amino acids of Ets-1 protein are predominant in ETS-GGAA but less so or absent in the mutant. These motions are reflected in the flexibility of amino acid residues of the protein backbone. We consider that these conformational features and water contacts are involved in stabilizing the hydrogen bond interactions between helix-3 residues of Ets-1 and DNA during the transcription process.

Amino Acid Sequence↗