Conformational Space Comparison of GnRH and lGnRH-III using Molecular Dynamics, Cluster Analysis and Monte Carlo Thermodynamic Integration

Watts, Charles R.; Mezei, Mihaly; Murphy, Richard F.; Lovas, Sándor

doi:10.1080/07391102.2001.10506703

Cited by 15 publications

(29 citation statements)

References 22 publications

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“…The two molecules differ in sequence at amino acid positions 5 -8, which confers distinct conformational characteristics that may account for differences in biological activity (Watts et al 2001). Yu et al (2000) reported selective FSH-releasing activity in fractions of gel-purified hypothalamic extracts that could be neutralized by antisera against lGnRH and proposed that the putative FSH-RH fractions were lGnRH-III or a closely related peptide.…”

Section: Discussionmentioning

confidence: 99%

Evidence that lamprey GnRH-III does not release FSH selectively in cattle

Amstalden¹,

Zieba²,

Garcia³

et al. 2004

Reproduction

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Experiments were performed to test the hypothesis that lamprey GnRH-III (lGnRH-III) selectively releases FSH. Primary cultures of bovine adenohypophyseal cells were treated with mammalian GnRH (mGnRH) and lGnRH-III (10 29 , 10 28, 10 27and 10 26 M) or control media in Experiment 1. All doses of mGnRH and the two highest doses of lGnRH-III stimulated (P < 0.001) a non-selective release of LH and FSH. In Experiments 2 -4, Latin Square designs were utilized in vivo to examine whether physiological and hormonal milieu regulate putative selective effects of lGnRH-III. In Experiments 2 and 3, ovariectomized cows with basal levels of estradiol only (Experiment 2) or in combination with luteal phase levels of progesterone (Experiment 3) were injected with mGnRH and lGnRH-III (0.055, 0.11, 0.165 and 1.1 mg/kg body weight (BW) and saline. All doses of mGnRH released (P < 0.001) LH and FSH, but only the highest dose of lGnRH-III stimulated (P < 0.001) a non-selective release of both LH and FSH (Experiment 3). For Experiments 4A and 4B, intact, mid-luteal phase cows were injected with mGnRH and lGnRH-III (1.1 mg/kg BW; Experiment 4A), lGnRH-III (1.1 and 4.4 mg/kg BW; Experiment 4B) and saline. As before, mGnRH released (P < 0.001) both LH and FSH at all doses. In contrast, lGnRH-III at the highest dose released (P < 0.001) LH but not FSH. These findings suggest that lGnRH-III may act as a weak competitor for the mGnRH receptor and do not support the hypothesis that it selectively releases FSH in cattle.

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Section: Discussionmentioning

confidence: 99%

Evidence that lamprey GnRH-III does not release FSH selectively in cattle

Amstalden¹,

Zieba²,

Garcia³

et al. 2004

Reproduction

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“…This quantity refers to the projection angle between the transition dipole moments of the two porphyrins running in the 5−15 direction (defined as in Figures and ), , which is indicative of the sign of the expected exciton couplet, that is, a positive twist leads to a positive couplet, and vice versa. Following an approach similar to cluster-type analysis, we plotted distribution graphs of θ values among all minima within 10 kJ/mol, corresponding approximately to 30−40 optimized structures resulting from the MC calculations (3 times 1000 steps). In these graphs (Figure ), the preferred sign of projection angle θ for a given complex can be inferred by counting the total number of structures presenting positive and negative θ .…”

Section: Nmr Studies Of Host/guest Complexesmentioning

confidence: 99%

Absolute Configurational Assignments of Secondary Amines by CD-Sensitive Dimeric Zinc Porphyrin Host

et al. 2002

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A general chiroptical protocol for determination of absolute configuration of secondary amines including acyclic and cyclic aliphatic amines, aromatic amines, amino acids, and amino alcohols is described. The chiral substrate is linked to the achiral carrier moiety (3-N-Boc-amino-propyl-N-Boc-amino)acetic acid 1 (BocHNCH(2)CH(2)CH(2)BocNCH(2)COOH), which after deprotection, yields a bidentate conjugate, capable of forming a 1:1 host/guest complex with dimeric zinc porphyrin host 2. As in the cases of primary amines and secondary alcohols reported earlier, the complexation of secondary amine conjugates to porphyrin tweezer host 2 represents a stereodifferentiating process, where the large (L) group at the stereogenic center (assigned on the basis of conformational energies A value) protrudes from the porphyrin binding pocket. This leads to formation of host/guest complexes with a preferred porphyrin helicity that exhibit intense exciton split CD spectra. It was found that the chiral sense of porphyrin twist is clearly controlled by the stereogenic center despite the Z/E conformational complexity around the tertiary amide bond of secondary amine conjugates that has greatly hampered previous configurational assignments. Thus, in cases where there is no ambiguity regarding the relative steric size of substituents, the observed CD couplet can be applied for straightforward assignment of absolute configurations. In addition, to extend the application to more difficult cases a molecular mechanics calculation approach using the Merck Molecular Force Field (MMFFs) was developed; this provides conformational information of host/guest complexes and leads to prediction of preferred porphyrin helicity independent of conformational A values. This chiroptical protocol in combination with molecular modeling represents a general method for configurational assignments of secondary amines.

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“…The use of clustering algorithms to group together similar conformations visited during a MD simulation is not a novel concept. ,, A wide variety of algorithms has been applied in many studies to cluster molecular dynamics trajectories, group similar conformations, and otherwise search for similarities among structures. A subset of publications developing and applying clustering algorithms to analyze molecular dynamics trajectories spans the range from some of the earliest MD simulations to very recent studies. ,,− In this work we build on the previous studies by comparing and contrasting the performance of various well-known clustering algorithms applied to the points in a plane example and multiple different sets of MD simulation data. The algorithms implemented include top-down/divisive ( hierarchical ), bottom-up/agglomerative (single-linkage/ edge -joining, centripetal , complete-linkage , centroid-linkage , average-linkage , and centripetal-complete ), refinement ( means , Bayesian , and self-organizing maps or SOM ), and tree clustering ( COBWEB ) algorithms.…”

Section: Introductionmentioning

confidence: 99%

Clustering Molecular Dynamics Trajectories: 1. Characterizing the Performance of Different Clustering Algorithms

Shao

Tanner

Thompson

et al. 2007

J. Chem. Theory Comput.

741

791

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Molecular dynamics simulation methods produce trajectories of atomic positions (and optionally velocities and energies) as a function of time and provide a representation of the sampling of a given molecule's energetically accessible conformational ensemble. As simulations on the 10-100 ns time scale become routine, with sampled configurations stored on the picosecond time scale, such trajectories contain large amounts of data. Data-mining techniques, like clustering, provide one means to group and make sense of the information in the trajectory. In this work, several clustering algorithms were implemented, compared, and utilized to understand MD trajectory data. The development of the algorithms into a freely available C code library, and their application to a simple test example of random (or systematically placed) points in a 2D plane (where the pairwise metric is the distance between points) provide a means to understand the relative performance. Eleven different clustering algorithms were developed, ranging from top-down splitting (hierarchical) and bottom-up aggregating (including single-linkage edge joining, centroid-linkage, average-linkage, complete-linkage, centripetal, and centripetal-complete) to various refinement (means, Bayesian, and self-organizing maps) and tree (COBWEB) algorithms. Systematic testing in the context of MD simulation of various DNA systems (including DNA single strands and the interaction of a minor groove binding drug DB226 with a DNA hairpin) allows a more direct assessment of the relative merits of the distinct clustering algorithms. Additionally, means to assess the relative performance and differences between the algorithms, to dynamically select the initial cluster count, and to achieve faster data mining by "sieved clustering" were evaluated. Overall, it was found that there is no one perfect "one size fits all" algorithm for clustering MD trajectories and that the results strongly depend on the choice of atoms for the pairwise comparison. Some algorithms tend to produce homogeneously sized clusters, whereas others have a tendency to produce singleton clusters. Issues related to the choice of a pairwise metric, clustering metrics, which atom selection is used for the comparison, and about the relative performance are discussed. Overall, the best performance was observed with the average-linkage, means, and SOM algorithms. If the cluster count is not known in advance, the hierarchical or average-linkage clustering algorithms are recommended. Although these algorithms perform well, it is important to be aware of the limitations or weaknesses of each algorithm, specifically the high sensitivity to outliers with hierarchical, the tendency to generate homogenously sized clusters with means, and the tendency to produce small or singleton clusters with average-linkage.

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Conformational Space Comparison of GnRH and lGnRH-III using Molecular Dynamics, Cluster Analysis and Monte Carlo Thermodynamic Integration

Cited by 15 publications

References 22 publications

Evidence that lamprey GnRH-III does not release FSH selectively in cattle

Evidence that lamprey GnRH-III does not release FSH selectively in cattle

Absolute Configurational Assignments of Secondary Amines by CD-Sensitive Dimeric Zinc Porphyrin Host

Clustering Molecular Dynamics Trajectories: 1. Characterizing the Performance of Different Clustering Algorithms

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