385 research outputs found
A proposal for regularly updated review/survey articles: "Perpetual Reviews"
We advocate the publication of review/survey articles that will be updated
regularly, both in traditional journals and novel venues. We call these
"perpetual reviews." This idea naturally builds on the dissemination and
archival capabilities present in the modern internet, and indeed perpetual
reviews exist already in some forms. Perpetual review articles allow authors to
maintain over time the relevance of non-research scholarship that requires a
significant investment of effort. Further, such reviews published in a purely
electronic format without space constraints can also permit more pedagogical
scholarship and clearer treatment of technical issues that remain obscure in a
brief treatment.Comment: This is a draft white paper and we seek comments from the communit
Binding of Small-Molecule Ligands to Proteins: “What You See” Is Not Always “What You Get”
We review insights from computational studies of affinities of ligands binding to proteins. The power of structural biology is in translating knowledge of protein structures into insights about their forces, binding, and mechanisms. However, the complementary power of computer modeling is in showing “the rest of the story” (i.e., how motions and ensembles and alternative conformers and the entropies and forces that cannot be seen in single molecular structures also contribute to binding affinities). Upon binding to a protein, a ligand can bind in multiple orientations; the protein or ligand can be deformed by the binding event; waters, ions, or cofactors can have unexpected involvement; and conformational or solvation entropies can sometimes play large and otherwise unpredictable roles. Computer modeling is helping to elucidate these factors
Kinetics and Free Energy of Ligand Dissociation Using Weighted Ensemble Milestoning
We consider the recently developed weighted ensemble milestoning (WEM) scheme
[J. Chem. Phys. 152, 234114 (2020)], and test its capability of simulating
ligand-receptor dissociation dynamics. We performed WEM simulations on the
following host-guest systems: Na/Cl ion pair and 4-hydroxy-2-butanone
(BUT) ligand with FK506 binding protein (FKBP). As proof or principle, we show
that the WEM formalism reproduces the Na/Cl ion pair dissociation
timescale and the free energy profile obtained from long conventional MD
simulation. To increase accuracy of WEM calculations applied to kinetics and
thermodynamics in protein-ligand binding, we introduced a modified WEM scheme
called weighted ensemble milestoning with restraint release (WEM-RR), which can
increase the number of starting points per milestone without adding additional
computational cost. WEM-RR calculations obtained a ligand residence time and
binding free energy in agreement with experimental and previous computational
results. Moreover, using the milestoning framework, the binding time and rate
constants, dissociation constant and the committor probabilities could also be
calculated at a low computational cost. We also present an analytical approach
for estimating the association rate constant () when binding is
primarily diffusion driven. We show that the WEM method can efficiently
calculate multiple experimental observables describing ligand-receptor
binding/unbinding and is a promising candidate for computer-aided inhibitor
design
Draft genome sequences of five recent human uropathogenic Escherichia coli isolates
This study reports the release of draft genome sequences of five isolates of uropathogenic Escherichia coli (UPEC), isolated from patients suffering from uncomplicated cystitis in 2012 in Ann Arbor, Michigan. Phylogenetic analyses revealed that these strains belonged to E. coli phylogroups B2 and D and are closely related to known UPEC strains. Comparative genomic analysis revealed that more conserved proteins were shared between these recent isolates and UPEC strains causing cystitis than those causing pyelonephritis. Additional genomic comparisons identified that three isolates encode a type III secretion system (T3SS) and a putative T3SS effector gene cluster along with an invasin‐like outer membrane protein. The presence of T3SS genes is a rare occurrence among UPEC strains. These genomes further substantiate the heterogeneity of the gene pool of UPEC and provide a foundation for comparative genomic studies using recent clinical isolates.This publication briefly describes the draft genomes of five recent human uropathogenic (UPEC) Escherichia coli isolates. UPEC are of increasing importance to human health. The genomes of these new isolates are clearly and simply described and will be of great utility and interest to this research community.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136326/1/fim12059.pd
Challenges in the use of atomistic simulations to predict solubilities of drug-like molecules [version 2; referees: 2 approved]
Background: Solubility is a physical property of high importance to the pharmaceutical industry, the prediction of which for potential drugs has so far been a hard task. We attempted to predict the solubility of acetylsalicylic acid (ASA) by estimating the absolute chemical potentials of its most stable polymorph and of solutions with different concentrations of the drug molecule. Methods: Chemical potentials were estimated from all-atom molecular dynamics simulations. We used the Einstein molecule method (EMM) to predict the absolute chemical potential of the solid and solvation free energy calculations to predict the excess chemical potentials of the liquid-phase systems. Results: Reliable estimations of the chemical potentials for the solid and for a single ASA molecule using the EMM required an extremely large number of intermediate states for the free energy calculations, meaning that the calculations were extremely demanding computationally. Despite the computational cost, however, the computed value did not agree well with the experimental value, potentially due to limitations with the underlying energy model. Perhaps better values could be obtained with a better energy model; however, it seems likely computational cost may remain a limiting factor for use of this particular approach to solubility estimation. Conclusions: Solubility prediction of drug-like solids remains computationally challenging, and it appears that both the underlying energy model and the computational approach applied may need improvement before the approach is suitable for routine use
Simulations of Oligomeric Intermediates in Prion Diseases
We extend our previous stochastic cellular automata based model for areal
aggregation of prion proteins on neuronal surfaces. The new anisotropic model
allow us to simulate both strong beta-sheet and weaker attachment bonds between
proteins. Constraining binding directions allows us to generate aggregate
structures with the hexagonal lattice symmetry found in recently observed in
vitro experiments. We argue that these constraints on rules may correspond to
underlying steric constraints on the aggregation process. We find that monomer
dominated growth of the areal aggregate is too slow to account for some
observed doubling time-to-incubation time ratios inferred from data, and so
consider aggregation dominated by relatively stable but non-infectious
oligomeric intermediates. We compare a kinetic theory analysis of oligomeric
aggregation to spatially explicit simulations of the process. We find that with
suitable rules for misfolding of oligomers, possibly due to water exclusion by
the surrounding aggregate, the resulting oligomeric aggregation model maps onto
our previous monomer aggregation model. Therefore it can produce some of the
same attractive features for the description of prion incubation time data. We
propose experiments to test the oligomeric aggregation model.Comment: 8 pages, 10 figures For larger versions of several figures, see
http://asaph.ucdavis.edu/~dmobley and click on the prion paper lin
Hydration free energies in the FreeSolv database calculated with polarized iterative Hirshfeld charges
Computer simulations of biomolecular systems often use force fields, which are combinations of simple empirical atom-based functions to describe the molecular interactions. Even though polarizable force fields give a more detailed description of intermolecular interactions, nonpolarizable force fields, developed several decades ago, are often still preferred because of their reduced computation cost. Electrostatic interactions play a major role in biomolecular systems and are therein described by atomic point charges. In this work, we address the performance of different atomic charges to reproduce experimental hydration free energies in the FreeSolv database in combination with the GAFF force field. Atomic charges were calculated by two atoms-in-molecules approaches, Hirshfeld-I and Minimal Basis Iterative Stockholder (MBIS). To account for polarization effects, the charges were derived from the solute’s electron density computed with an implicit solvent model, and the energy required to polarize the solute was added to the free energy cycle. The calculated hydration free energies were analyzed with an error model, revealing systematic errors associated with specific functional groups or chemical elements. The best agreement with the experimental data is observed for the AM1-BCC and the MBIS atomic charge methods. The latter includes the solvent polarization and presents a root-mean-square error of 2.0 kcal mol–1 for the 613 organic molecules studied. The largest deviation was observed for phosphorus-containing molecules and the molecules with amide, ester and amine functional groups
Brewster-angle measurements of sea-surface reflectance using a high resolution spectroradiometer
This paper describes the design, construction and testing of a ship-borne spectroradiometer based on an imaging spectrograph and cooled CCD array with a wavelength range of 350-800 nm and 4 nm spectral sampling. The instrument had a minimum spectral acquisition time of 0.1 s, but in practice data were collected over periods of 10 s to allow averaging of wave effects. It was mounted on a ship's superstructure so that it viewed the sea surface from a height of several metres at the Brewster angle (53 degrees) through a linear polarizing filter. Comparison of sea-leaving spectra acquired with the polarizer oriented horizontally and vertically enabled estimation of the spectral composition of sky light reflected directly from the sea surface. A semi-empirical correction procedure was devised for retrieving water-leaving radiance spectra from these measurements while minimizing the influence of reflected sky light. Sea trials indicated that reflectance spectra obtained by this method were consistent with the results of radiance transfer modelling of case 2 waters with similar concentrations of chlorophyll and coloured dissolved organic matter. Surface reflectance signatures measured at three locations containing blooms of different phytoplankton species were easily discriminated and the instrument was sufficiently sensitive to detect solar-stimulated fluorescence from surface chlorophyll concentrations down to 1 mg m−3
Reproducibility of Free Energy Calculations Across Different Molecular Simulation Software
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<p>Alchemical free energy calculations are an increasingly important modern simulation
technique. Contemporary molecular simulation software such as AMBER, CHARMM,
GROMACS and SOMD include support for the method. Implementation details vary
among those codes but users expect reliability and reproducibility, i.e. for a given molec-
ular model and set of forcefield parameters, comparable free energy should be obtained within statistical bounds regardless of the code used. Relative alchemical free energy
(RAFE) simulation is increasingly used to support molecule discovery projects, yet the
reproducibility of the methodology has been less well tested than its absolute counter-
part. Here we present RAFE calculations of hydration free energies for a set of small
organic molecules and demonstrate that free energies can be reproduced to within about
0.2 kcal/mol with aforementioned codes. Achieving this level of reproducibility requires
considerable attention to detail and package–specific simulation protocols, and no uni-
versally applicable protocol emerges. The benchmarks and protocols reported here
should be useful for the community to validate new and future versions of software for
free energy calculations.</p></div></div></div
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