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 ($k_{\text{on}}$) 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

<div> <div> <div> <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