We have optimized and extended the widely used annotation engine MAKER in order to better support plant genome annotation efforts. New features include better parallelization for large repeat-rich plant genomes, noncoding RNA annotation capabilities, and support for pseudogene identification. We have benchmarked the resulting software tool kit, MAKER-P, using the Arabidopsis (Arabidopsis thaliana) and maize (Zea mays) genomes. Here, we demonstrate the ability of the MAKER-P tool kit to automatically update, extend, and revise the Arabidopsis annotations in light of newly available data and to annotate pseudogenes and noncoding RNAs absent from The Arabidopsis Informatics Resource 10 build. Our results demonstrate that MAKER-P can be used to manage and improve the annotations of even Arabidopsis, perhaps the best-annotated plant genome. We have also installed and benchmarked MAKER-P on the Texas Advanced Computing Center. We show that this public resource can de novo annotate the entire Arabidopsis and maize genomes in less than 3 h and produce annotations of comparable quality to those of the current The Arabidopsis Information Resource 10 and maize V2 annotation builds.
The alkaline earth metals calcium and magnesium are critically involved in many biomolecular processes. To understand the hydration thermodynamics of these ions, we have performed molecular dynamics simulations using a polarizable potential. Particle-mesh Ewald for point multipoles has been applied to the calculation of electrostatic interactions. The parameters in this model have been determined from an ab initio quantum mechanical calculation of dimer interactions between ions and water. Two methods for ion solvation free energy calculation, free energy perturbation, and the Bennett acceptance ratio have been compared. Both predict results consistent with other theoretical estimations while the Bennett approach leads to a much smaller statistical error. Based on the Born theory and the ion-oxygen radial distribution functions, we estimate the effective size of the ions in solution, concluding that K(+) > Na(+) congruent with Ca(2+) > Mg(2+). There appears to be much stronger perturbation in water structure, dynamics, and dipole moment around the divalent cations than the monovalent K(+) and Na(+). The average water coordination numbers for Ca(2+) and Mg(2+) are 7.3 and 6, respectively. The lifetime of water molecules in the first solvation shell of Mg(2+) is on the order of hundreds of picoseconds, in contrast to only few picoseconds for Ca(2+), K(+), or Na(+).
The binding of charged ligands benzamidine and diazamidine to trypsin was investigated by using a polarizable potential energy function and explicit-water molecular dynamics simulations. The binding free energies were computed from the difference between the free energies of decoupling the ligand from water and protein environments. Both the absolute and the relative free energies from the perturbation simulations agree with experimental measurements to within 0.5 kcal⅐mol ؊1 . Comparison of free-energy components sampled from different thermodynamic paths indicates that electrostatics is the main driving force behind benzamidine recognition of trypsin. The contribution of electronic polarization to binding appears to be crucial. By computing the free-energy contribution caused by the polarization between the ligand and its surroundings, we found that polarization has the opposite effect in dissimilar environments. Although polarization favors ligand solvation in water, it weakens the protein-ligand attraction by screening the electrostatic interaction between trypsin and benzamidine. We also examined the relative binding free energies of a benzamidine analog diazamidine to trypsin. The changes in free energy on benzamidine-diazamidine substitution were tens of kilocalories in both water and trypsin environments; however, the change in the total binding free energy is <2 kcal⅐mol ؊1 because of cancellation, consistent with the experimental results. Overall, our results suggest that the use of a polarizable force field, given adequate sampling, is capable of achieving chemical accuracy in molecular simulations of protein-ligand recognition.simulation ͉ molecular dynamics ͉ trypsin ͉ benzamidine ͉ force field S pecific recognition of ligands by proteins is at the core of many crucial biological functions and systems such as enzyme catalysis and intracellular signaling. Binding affinity characterizes the strength of such recognition. With the recent advancements in computing, prediction of the binding affinity based on physical principles of molecular interaction has come to the forefront of active research and has been the subject of regular reviews (1-5). All-atom molecular dynamics (MD) simulation with explicit solvent, coupled with efficient free-energy sampling algorithms, can potentially offer accurate prediction of binding free energies of ligands to proteins (5). Common free-energy simulation algorithms include the double-decoupling method (DDM) and potential of mean force approach (PMF). Free-energy perturbation (FEP), thermodynamic integration (TI), or umbrella sampling can be used to compute free-energy differences in either DDM or PMF. It has been argued that DDM is problematic for charged systems, because the binding free energy is computed as a small difference between two large solvation energies in water and in protein (6). However, the PMF approach does not quantify absolute solvation energies of ligand, which makes it difficult to detect potential problems in treatment of long-range effect and bou...
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