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Crystal structures of nematode (parasitic T. spiralis and free living C. elegans), compared to mammalian, thymidylate synthases (TS). Molecular docking and molecular dynamics simulations in search for nematode-specific inhibitors of TS

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... The C-terminus of subunit A is stabilized by crystal contacts with several residues from the neighboring TS dimer (Figure 4). The lack of clearly defined electron density for the final few (four in this case) residues of the C-terminus of subunit B has been observed previously for several structures of TS complexes, e.g., rat TS-dUMP-Tomudex (PDB ID: 1RTS and 2TSR [17]), CeTS-dUMP-Tomudex (PDB ID: 5NOO [18]), and mTS-dUMP-Tomudex (PDB ID: 4EB4 [19]). Spatial orientation of His190 present in the 4EZ8 structure (or of the corresponding histidine residue in any other specific variant of TS) is also found in multiple other structures of the mouse enzyme, e.g., 4EIN (mTS-N 4 -OH-dCMP complex [14]), 4E5O (mTS-dUMP [20]), 6F6Z (mTS-N 4 -OH-dCMP soaked with meTHF), 4EB4 (mTS-dUMP-Tomudex [19]), 3IHI (mTS apoenzyme [13]), and as one of two alternative conformations in 5BY6 (TspTS-dUMP [18,21]). ...
... The lack of clearly defined electron density for the final few (four in this case) residues of the C-terminus of subunit B has been observed previously for several structures of TS complexes, e.g., rat TS-dUMP-Tomudex (PDB ID: 1RTS and 2TSR [17]), CeTS-dUMP-Tomudex (PDB ID: 5NOO [18]), and mTS-dUMP-Tomudex (PDB ID: 4EB4 [19]). Spatial orientation of His190 present in the 4EZ8 structure (or of the corresponding histidine residue in any other specific variant of TS) is also found in multiple other structures of the mouse enzyme, e.g., 4EIN (mTS-N 4 -OH-dCMP complex [14]), 4E5O (mTS-dUMP [20]), 6F6Z (mTS-N 4 -OH-dCMP soaked with meTHF), 4EB4 (mTS-dUMP-Tomudex [19]), 3IHI (mTS apoenzyme [13]), and as one of two alternative conformations in 5BY6 (TspTS-dUMP [18,21]). On the other hand, an alternative orientation of His190 present in the 5M4Z structure is also observed in several other structures, including 5BY6 (as the other alternative conformation with 0.6 occupancy), 4PSG (CeTS-N 4 -OH-dCMP complex), 5NOO (CeTS-dUMP-Tomudex [18]), 5FCT (mTS-FdUMP-meTHF [13]), 4IRR (CeTS-dUMP [19]), 4IQB (CeTS apoenzyme [18]), and 4ISW (phosphorylated CeTS-dUMP [22]). ...
... Spatial orientation of His190 present in the 4EZ8 structure (or of the corresponding histidine residue in any other specific variant of TS) is also found in multiple other structures of the mouse enzyme, e.g., 4EIN (mTS-N 4 -OH-dCMP complex [14]), 4E5O (mTS-dUMP [20]), 6F6Z (mTS-N 4 -OH-dCMP soaked with meTHF), 4EB4 (mTS-dUMP-Tomudex [19]), 3IHI (mTS apoenzyme [13]), and as one of two alternative conformations in 5BY6 (TspTS-dUMP [18,21]). On the other hand, an alternative orientation of His190 present in the 5M4Z structure is also observed in several other structures, including 5BY6 (as the other alternative conformation with 0.6 occupancy), 4PSG (CeTS-N 4 -OH-dCMP complex), 5NOO (CeTS-dUMP-Tomudex [18]), 5FCT (mTS-FdUMP-meTHF [13]), 4IRR (CeTS-dUMP [19]), 4IQB (CeTS apoenzyme [18]), and 4ISW (phosphorylated CeTS-dUMP [22]). ...
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Novel evidence is presented allowing further clarification of the mechanism of the slow-binding thymidylate synthase (TS) inhibition by N4-hydroxy-dCMP (N4-OH-dCMP). Spectrophotometric monitoring documented time- and temperature-, and N4-OH-dCMP-dependent TS-catalyzed dihydrofolate production, accompanying the mouse enzyme incubation with N4-OH-dCMP and N5,10-methylenetetrahydrofolate, known to inactivate the enzyme by the covalent binding of the inhibitor, suggesting the demonstrated reaction to be uncoupled from the pyrimidine C(5) methylation. The latter was in accord with the hypothesis based on the previously presented structure of mouse TS (cf. PDB ID: 4EZ8), and with conclusions based on the present structure of the parasitic nematode Trichinella spiralis, both co-crystallized with N4-OH-dCMP and N5,10-methylenetetrahdrofolate. The crystal structure of the mouse TS-N4-OH-dCMP complex soaked with N5,10-methylenetetrahydrofolate revealed the reaction to run via a unique imidazolidine ring opening, leaving the one-carbon group bound to the N(10) atom, thus too distant from the pyrimidine C(5) atom to enable the electrophilic attack and methylene group transfer.
... Overall, both compounds proved to bind within the TS catalytic site, in close proximity and in stacking conformation to the co-crystallized dUMP cofactor. Notably, both compounds adopted a very similar binding mode against the catalytic site of TS from both human and C. elegans, which is not surprising according to the high degree of sequence and structural identity between TS from the two species [48]. Besides stacking to dUMP, the major anchor point is the side chain of Asp220 (in C. elegans Ts) or Asp 218 (in human TS), which is H-bonded to a hydroxyl group connected to the xanthone ring ( Figure 5). ...
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With the aim to identify novel inhibitors of parasitic nematode thymidylate synthase (TS), we screened in silico an in-house library of natural compounds, taking advantage of a model of nematode TS three-dimensional (3D) structure and choosing candidate compounds potentially capable of enzyme binding/inhibition. Selected compounds were tested as (i) inhibitors of the reaction catalyzed by TSs of different species, (ii) agents toxic to a nematode parasite model (C. elegans grown in vitro), (iii) inhibitors of normal human cell growth, and (iv) antitumor agents affecting human tumor cells grown in vitro. The results pointed to alvaxanthone as a relatively strong TS inhibitor that causes C. elegans population growth reduction with nematocidal potency similar to the anthelmintic drug mebendazole. Alvaxanthone also demonstrated an antiproliferative effect in tumor cells, associated with a selective toxicity against mitochondria observed in cancer cells compared to normal cells.
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Endogenous thymidylate synthases, isolated from tissues or cultured cells of the same specific origin, have been reported to show differing slow-binding inhibition patterns. These were reflected by biphasic or linear dependences of the inactivation rate on time and accompanied by differing inhibition parameters. Considering importance for chemotherapeutic drug resistance, a possibility was tested of thymidylate synthase inhibition to be affected by post-translational modification, e.g. phosphorylation, by comparing sensitivities to inhibition by each of two slow-binding inhibitors, 5-fluoro-dUMP and N4-hydroxy-dCMP, of two fractions of purified recombinant mouse enzyme preparation, phosphorylated and non-phosphorylated, separated by metal oxide/hydroxide affinity chromatography on Al(OH)3 beads. The modification, found to concern histidine residues and influence kinetic properties by lowering Vmax, altered with each inhibitor studied both the pattern of the dependence of the inactivation rate on time from linear to biphasic, as well as slow-binding inhibition parameters. Being present on only one subunit of at least a great majority of phosphorylated enzyme molecules, it probably introduced dimer asymmetry, causing the altered time dependence of inactivation rate pattern (biphasic with the phosphorylated enzyme) and resulting in asymmetric binding of each inhibitor studied. The latter is reflected by the ternary complexes, stable under denaturing conditions, formed by only the non-phosphorylated subunit of the phosphorylated enzyme with each of the two inhibitors and N5,10-methylenetetrahydrofolate. Inhibition of the phosphorylated enzyme by N4-hydroxy -dCMP was found strongly dependent on [Mg2+], the cations demonstrated previously to influence also activity of endogenous mouse TS isolated from tumour cells.
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Our current understanding of the mechanisms of action of antitumor agents and the precise mechanisms underlying drug resistance is that these two processes are directly linked. Moreover, it is often possible to delineate chemoresistance mechanisms based on the specific mechanism of action of a given anticancer drug. A more holistic approach to the chemoresistance problem suggests that entire metabolic pathways, rather than single enzyme targets may better explain and educate us about the complexity of the cellular responses upon cytotoxic drug administration. Drugs, which target thymidylate synthase and folate-dependent enzymes, represent an important therapeutic arm in the treatment of various human malignancies. However, prolonged patient treatment often provokes drug resistance phenomena that render the chemotherapeutic treatment highly ineffective. Hence, strategies to overcome drug resistance are primarily designed to achieve either enhanced intracellular drug accumulation, to avoid the upregulation of folate-dependent enzymes, and to circumvent the impairment of DNA repair enzymes which are also responsible for cross-resistance to various anticancer drugs. The current clinical practice based on drug combination therapeutic regimens represents the most effective approach to counteract drug resistance. In the current paper, we review the molecular aspects of the activity of TS-targeting drugs and describe how such mechanisms are related to the emergence of clinical drug resistance. We also discuss the current possibilities to overcome drug resistance by using a molecular mechanistic approach based on medicinal chemistry methods focusing on rational structural modifications of novel antitumor agents. This paper also focuses on the importance of the modulation of metabolic pathways upon drug administration, their analysis and the assessment of their putative roles in the networks involved using a meta-analysis approach. The present review describes the main pathways that are modulated by TS-targeting anticancer drugs starting from the description of the normal functioning of the folate metabolic pathway, through the protein modulation occurring upon drug delivery to cultured tumor cells as well as cancer patients, finally describing how the pathways are modulated by drug resistance development. The data collected are then analyzed using network/netwire connecting methods in order to provide a wider view of the pathways involved and of the importance of such information in identifying additional proteins that could serve as novel druggable targets for efficacious cancer therapy.
Article
Many questions about the biological activity and availability of small molecules remain inaccessible to investigators who could most benefit from their answers. To narrow the gap between chemoinformatics and biology, we have developed a suite of ligand annotation, purchasability, target and biology association tools, incorporated into ZINC and meant for investigators who are not computer specialists. The new version contains over 120 million purchasable "drug-like" compounds - effectively all organic molecules that are for sale - a quarter of which are available for immediate delivery. ZINC connects purchasable compounds to high-value ones such as metabolites, drugs, natural products and annotated compounds from the literature. Compounds may be accessed by the genes they are annotated for, as well as the major and minor target classes to which those genes belong. It offers new analysis tools that are easy for non-specialists yet with few limitations for experts. ZINC retains its original 3D roots - all molecules are available in biologically relevant, ready-to-dock formats. ZINC is freely available at zinc15.docking.org.
Article
Recently, octapeptide LSCQLYQR (LRp), reducing growth of cis-platinum (cDDP) resistant ovarian carcinoma cells by inhibiting the monomer-monomer interface of the human enzyme thymidylate synthase, has been identified. As the peptide is not able to cross the cell membrane it requires an appropriate delivery system. In this work the application of SLNs, biocompatible and efficient tools for the intracellular drug transport, applied especially for lipophilic drugs, was exploited for the delivery of the hydrophilic peptide LRp. SLNs formulated in the absence/presence of small amount of squalene showed dimensions below 150nm, negative zeta potential and good stability to the freeze-drying process. Even though the particles formulated with squalene exhibited a less ordered crystal lattice and a lower surface hydrophobicity, a rapid drug release from these nanocarriers occurred as a result of the relevant expulsion of the drug from the lipid core during lipid crystallization. On the contrary, SLNs formulated in the absence of squalene were able to incorporate more stably the peptide showing considerable cytotoxic effect on cDDP resistant C13* ovarian carcinoma cell line at concentration 50 times lower than that used previously with a marketed delivery system. From the cell cycle analysis by the propidium iodide test in SLNs-peptide treated cancer cells an increase of apoptosis percentage was observed, indicating that SLNs were able to carry efficiently the peptide until its enzymatic target.
Article
Because of the availability of large compound collections on the Web, elementary cheminformatics tasks such as chemical library browsing, analyzing, filtering, or unifying have become widespread in the life science community. Furthermore, the high performance of desktop hardware allows an interactive, problem-driven approach to these tasks, avoiding rigid processing scripts and workflows. Here, we present MONA 2, which is the second major release of our cheminformatics desktop application addressing this need. Using MONA requires neither complex database setups nor expert knowledge of cheminformatics. A new molecular set concept purely based on structural entities rather than individual compounds has allowed the development of an intuitive user interface. Based on a chemically precise, high-performance software library, typical tasks on chemical libraries with up to one million compounds can be performed mostly interactively. This paper describes the functionality of MONA, its fundamental concepts, and a collection of application scenarios ranging from file conversion, compound library curation, and management to the post-processing of large-scale experiments.
Article
Molecular mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Average errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a physically motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but also improved secondary structure content in small peptides and reproduction of NMR χ1 scalar coupling measurements for proteins in solution. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements.
Article
For a little over a decade now, the Macromolecular Crystallography (MX) group at the Helmholtz-Zentrum Berlin (HZB) has been operating three state-of-the-art synchrotron beamlines for MX at the BESSY II storage ring in Berlin. The three HZB-MX beamlines, BL14.1, BL14.2 and BL14.3, serve a stable and growing user community of currently more than 100 independent research groups from Berlin, Germany and Europe. Every year, the beamlines provide close to 200 days of MX-beamtime. Over time, the HZB-MX beamlines and endstations, in particular BL14.1, have been continually developed and upgraded and, since 2010, they operate as the most productive MX beamlines in Germany. The environment of the beamlines includes various ancillary equipment as well as additional facilities, such as office space adjacent to the beamlines, a sample preparation laboratory, a safety level 1 biology laboratory (HZB-MX BioLab) and all necessary computing resources. In this paper, the current status of the beamlines as well as the ongoing developments are described.
Article
Information on the cellular internalization and stability of the ovarian cancer cell growth inhibitor peptide, LSCQLYQR (LR), is vital for lead optimization. Ad-hoc-synthesized LR/fluorescent-probe conjugates were used to monitor the internalization of the peptide. Mass spectrometry was used to identify adducts resulting from the thiol reactivity of the cysteine residue in LR. A mechanistic model is proposed to explain the observed change in intracellular peptide amount over time. Structural modifications can be foreseen to improve the peptide stability.
Article
Thymidylate synthase (TS) is a target for pemetrexed and the prodrug 5-fluorouracil (5-FU) that inhibit the protein by binding at its active site. Prolonged administration of these drugs causes TS overexpression, leading to drug resistance. The peptide lead, LR (LSCQLYQR), allosterically stabilizes the inactive form of the protein, and inhibits ovarian cancer (OC) cell growth with stable TS and decreased dihydrofolate reductase (DHFR) expression. To improve TS inhibition and the anticancer effect, we have developed 35 peptides by modifying the lead. The D-glutamine-modified peptide displayed the best inhibition of cisplatin-sensitive and -resistant OC cell growth, was more active than LR and 5-FU, and showed TS/DHFR expression pattern similar to LR. CD spectroscopy and molecular dynamics studies provided a molecular-level rationale for the differences in structural preferences and the enzyme inhibitory activities. By combining target inhibition studies and associated proteins modulation pattern, this work avenues a concept to develop more specific inhibitors of OC cell growth and drug leads.
Article
Many hundreds of millions of people throughout the world are infected by nematodes found in the intestine or tissues with a high prevalence in developing countries. Despite their frequency and morbidity, these infections, which may affect migrants and travelers, remain difficult to diagnosis even in developed countries. This is primarily due to the variety of clinical signs often associated with a lack of highly sensitive and specific diagnostic tools. Parasitological diagnosis is often difficult to achieve and can neither be applied during the pre-patent period nor for parasitic impasses. Serological diagnosis is frequently hampered by a lack of specificity due to cross-reaction with others helminthes. Molecular biology methods still require optimization. The diagnostic approach applied by a clinician of a suspected nematode infection is based on a vast set of data including patient history and way of life, clinical examination, non-specific biological tests and, when available, specific diagnostic tests.
Article
Thymidylate synthase (TS) is a target for antifolate-based chemotherapies of microbial and human diseases. Here, ligand-based, synthetic and X-ray crystallography studies led to the discovery of 6-(3-cyanobenzoyloxy)-2-oxo-2H-naphto[1,8-bc]furan, a novel inhibitor with a Ki of 310 nM against Pneumocystis carinii TS. The X-ray ternary complex with Escherichia coli TS revealed, for the first time, displacement of the substrate towards the dimeric protein interface, thus providing new opportunities for further design of specific inhibitors of microbial pathogens.
Article
Crystal structures of four pyrrolo(2,3-d)pyrimidine-based antifolate compounds, developed as inhibitors of thymidylate synthase (TS) in a strategy to circumvent drug-resistance, have been determined in complexes with their in vivo target, human thymidylate synthase, and with the structurally best-characterized Escherichia coli enzyme, to resolutions of 2.2-3.0 Å. The 2.9 Å crystal structure of a complex of human TS with one of the inhibitors, the multi-targeted antifolate LY231514, demonstrates that this compound induces a “closed” enzyme conformation and leads to formation of a covalent bond between enzyme and substrate. This structure is one of the first liganded human TS structures, and its solution was aided by mutation to facilitate crystallization. Structures of three other pyrrolo(2,3-d)pyrimidine-based antifolates in complex with Escherichia coli TS confirm the orientation of this class of inhibitors in the active site. Specific interactions between the polyglutamyl moiety and a positively charged groove on the enzyme surface explain the marked increase in affinity of the pyrrolo(2,3-d)pyrimidine inhibitors once they are polyglutamylated, as mediated in vivo by the cellular enzyme folyl polyglutamate synthetase.
Article
Structure-based drug design of species-specific inhibitors generally exploits structural differences in proteins from different organisms. Here, we demonstrate how achieving specificity can be aided by targeting differences in the dynamics of proteins. Thymidylate synthase (TS) is a good target for anticancer agents and a potential target for antibacterial agents. Most inhibitors are folate-analogs that bind at the folate binding site and are not species specific. In contrast, α156 is not a folate-analog and is specific for bacterial TS; it has been shown crystallographically to bind in a nonconserved binding site. Docking calculations and crystal structure-based estimation of the essential dynamics of TSs from five different species show that differences in the dynamics of TSs make the active site more accessible to α156 in the prokaryotic than in the eukaryotic TSs and thereby enhance the specificity of α156.
Article
The bifunctional enzyme thymidylate synthase-dihydrofolate reductase (TS-DHFR) plays an essential role in DNA synthesis and is unique to several species of pathogenic protozoans, including the parasite Toxoplasma gondii. Infection by T. gondii causes the prevalent disease toxoplasmosis, for which TS-DHFR is a major therapeutic target. Here, we design peptides that target the dimer interface between the TS domains of bifunctional T. gondii TS-DHFR by mimicking β-strands at the interface, revealing a previously unknown allosteric target. The current study shows that these β-strand mimetic peptides bind to the apo-enzyme in a species-selective manner to inhibit both the TS and distal DHFR. Fluorescence spectroscopy was used to monitor conformational switching of the TS domain and demonstrate that these peptides induce a conformational change in the enzyme. Using structure-guided mutagenesis, nonconserved residues in the linker between TS and DHFR were identified that play a key role in domain-domain communication and in peptide inhibition of the DHFR domain. These studies validate allosteric inhibition of apo-TS, specifically at the TS-TS interface, as a potential target for novel, species-specific therapeutics for treating T. gondii parasitic infections and overcoming drug resistance.
Article
We describe herein the design and development of an innovative tool called the NuBBE database (NuBBE(DB)), a new Web-based database, which incorporates several classes of secondary metabolites and derivatives from the biodiversity of Brazil. This natural product database incorporates botanical, chemical, pharmacological, and toxicological compound information. The NuBBE(DB) provides specialized information to the worldwide scientific community and can serve as a useful tool for studies on the multidisciplinary interfaces related to chemistry and biology, including virtual screening, dereplication, metabolomics, and medicinal chemistry. The NuBBE(DB) site is at http://nubbe.iq.unesp.br/nubbeDB.html .
Article
Phenolnaphthalein derivatives show potential for pharmacological activity as inhibitors of thymidylate synthase (TS) but difficulties in their synthesis and derivatization hinder their development. A deconstruction approach aimed at identifying a suitable new scaffold was proposed. A new scaffold was identified and two compound libraries based on this scaffold were designed. The carboxamide library (Library B) showed specific inhibition activity against Escherichia coli TS, whereas the sulfonamide library (Library C) showed a non-specific inhibition profile against hTS. N-(1,3-Dioxo-1H,3H-benzo[de]isochromen-5-yl)-sulfonamide derivatives, 1C and 9C, showed one order of magnitude improvement in inhibition constant against hTS with respect to the starting lead and represent potential compounds for further lead development.
Article
The estimation of free energy of binding is a key problem in structure-based design. We developed the scoring function HYDE based on a consistent description of HYdrogen bond and DEhydration energies in protein-ligand complexes. HYDE is applicable to all types of protein targets since it is not calibrated on experimental binding affinity data or protein-ligand complexes. The comprehensible atom-based score of HYDE is visualized by applying a very intuitive coloring scheme, thereby facilitating the analysis of protein-ligand complexes in the lead optimization process. In this paper, we have revised several aspects of the former version of HYDE which was described in detail previously. The revised HYDE version was already validated in large-scale redocking and screening experiments which were performed in the course of the Docking and Scoring Symposium at 241st ACS National Meeting. In this study, we additionally evaluate the ability of the revised HYDE version to predict binding affinities. On the PDBbind 2007 coreset, HYDE achieves a correlation coefficient of 0.62 between the experimental binding constants and the predicted binding energy, performing second best on this dataset compared to 17 other well-established scoring functions. Further, we show that the performance of HYDE in large-scale redocking and virtual screening experiments on the Astex diverse set and the DUD dataset respectively, is comparable to the best methods in this field.
Article
Simulations of the HIV‐1 protease unit cell using a 9 Å cutoff, 9/18 Å ‘‘twin‐range’’ cutoff, and full Ewald sums have been carried out to 300 ps. The results indicate that long‐range electrostaticinteractions are essential for proper representation of the HIV‐1 protease crystal structure. The 9 Å simulation did not converge in 300 ps. Inclusion of a 9/18 Å ‘‘twin‐range’’ cutoff showed significant improvement. Simulation using the Ewald summation convention gave the best overall agreement with x‐ray crystallographic data, and showed the least internal differences in the time average structures of the asymmetric units. The Ewald simulation represents an efficient implementation of the Particle Mesh Ewald method [Darden et al., J. Chem. Phys. 98, 10 089 (1993)], and illustrates the importance of including long‐range electrostatic forces in large macromolecular systems.
Article
Localization of thymidylate synthase protein in Trichinella spiralis and Caenorhabditis elegans development was followed with the use of confocal microscopy, revealing similar expression patterns in both nematode species. In T. spiralis premature muscle larvae and C. elegans dauer, L3 and L4 larvae, thymidylate synthase was detected in the nerve ring and gonad primordia, as well as T. spiralis stichosome and C. elegans pharyngeal glandular cells. In developmentally arrested T. spiralis muscle larvae, the enzyme was found localized to the gonad primordia and stichosome. High enzyme level was also observed in the embryos developing in uteri of T. spiralis female adult and C. elegans hermaphrodite forms. In the case of T. spiralis adult forms, thymidylate synthase was detected in stichosome, along esophagus wall, as well as in egg and sperm cells. While the enzyme protein present in the embryos remains in accord with its known association with proliferating systems, thymidylate synthase presence in the nerve ring, and reproductive and secretory (T. spiralis stichosomal and C. elegans pharyngeal glandular cells) systems, points to a state of cell cycle-arrest, also known to preserve the enzyme protein.
Article
A fast analytical formula was derived for the calculation of approximate atomic and molecular van der Waals (vdWSA), and solvent-accessible surface areas (SASAs), as well as the first and second derivatives of these quantities with respect to atomic coordinates. This method makes use of linear combinations of terms composed from pairwise overlaps of hard spheres; therefore, we term this the LCPO method for linear combination of pairwise overlaps. For higher performance, neighbor-list reduction (NLR) was applied as a preprocessing step. Eighteen compounds of different sizes (8–2366 atoms) and classes (organic, proteins, DNA, and various complexes) were chosen as representative test cases. LCPO/NLR computed the SASA and first derivatives of penicillopepsin, a protein with 2366 atoms, in 0.87 s (0.22 s for the creation of the neighbor list, 0.35 s for NLR, and 0.30 s for SASA and first derivatives) on an SGI R10000/194 Mhz processor. This appears comparable to or better than timings reported previously for other algorithms. The vdWSAs were in good agreement with the numerical results: relative errors for total molecular surface areas ranged from 0.1 to 2.0% and average absolute atomic surface area deviations from 0.3 to 0.7 Å2. For SASAs without NLR, the LCPO method exhibited relative errors in the range of 0.4–9.2% for total molecular surface areas and average absolute atomic surface area deviations of 2.0–2.7 Å2; with NLR the relative molecular errors ranged from 0.1 to 7.8% and the average absolute atomic surface area deviation from 1.6 to 3.0 Å2. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 217–230, 1999
Article
The AM1-BCC method quickly and efficiently generates high-quality atomic charges for use in condensed-phase simulations. The underlying features of the electron distribution including formal charge and delocalization are first captured by AM1 atomic charges for the individual molecule. Bond charge corrections (BCCs), which have been parameterized against the HF/6-31G* electrostatic potential (ESP) of a training set of compounds containing relevant functional groups, are then added using a formalism identical to the consensus BCI (bond charge increment) approach. As a proof of the concept, we fit BCCs simultaneously to 45 compounds including O-, N-, and S-containing functionalities, aromatics, and heteroaromatics, using only 41 BCC parameters. AM1-BCC yields charge sets of comparable quality to HF/6-31G* ESP-derived charges in a fraction of the time while reducing instabilities in the atomic charges compared to direct ESP-fit methods. We then apply the BCC parameters to a small “test set” consisting of aspirin, d-glucose, and eryodictyol; the AM1-BCC model again provides atomic charges of quality comparable with HF/6-31G* RESP charges, as judged by an increase of only 0.01 to 0.02 atomic units in the root-mean-square (RMS) error in ESP. Based on these encouraging results, we intend to parameterize the AM1-BCC model to provide a consistent charge model for any organic or biological molecule. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 132–146, 2000