Multi-Site λ-dynamics for simulated Structure-Activity Relationship studies.

Multi-Site λ-dynamics (MSλD) is a new free energy simulation method that is based on λ-dynamics. It has been developed to enable multiple substituents at multiple sites on a common ligand core to be modeled simultaneously and their free energies assessed. The efficacy of MSλD for estimating relative hydration free energies and relative binding affinties is demonstrated using three test systems.

Synthesis of chromans via Pd-catalyzed alkene carboetherification reactions.

A new method for the construction of 2-substituted and 2,2-disubstituted chromans via Pd-catalyzed carboetherification reactions between aryl/alkenyl halides and 2-(but-3-en-1-yl)phenols is described. These reactions effect formation of a C-O bond and a C-C bond to afford the chroman products in good yield, and also provide stereoselective access to tricyclic chroman derivatives.

Ion mobility-mass spectrometry reveals conformational changes in charge reduced multiprotein complexes.

Characterizing intact multiprotein complexes in terms of both their mass and size by ion mobility-mass spectrometry is becoming an increasingly important tool for structural biology. Furthermore, the charge states of intact protein complexes can dramatically influence the information content of gas-phase measurements performed. Specifically, protein complex charge state has a demonstrated influence upon the conformation, mass resolution, ion mobility resolution, and dissociation properties of protein assemblies upon collisional activation.

Palladium-Catalyzed Ligand-Directed Oxidative Functionalization of Cyclopropanes.

This report describes the Pd-catalyzed functionalization of cyclopropanes containing oxazoline, oxime ether, and pyridine directing groups. Three different oxidants were examined in these studies: IOAc, PhI(OAc), and benzoquinone. The reactions yielded products derived from 2° sp C-H functionalization and/or C-C activation of the cyclopropane ring.

Surveying implicit solvent models for estimating small molecule absolute hydration free energies.

Implicit solvent models are powerful tools in accounting for the aqueous environment at a fraction of the computational expense of explicit solvent representations. Here, we compare the ability of common implicit solvent models (TC, OBC, OBC2, GBMV, GBMV2, GBSW, GBSW/MS, GBSW/MS2 and FACTS) to reproduce experimental absolute hydration free energies for a series of 499 small neutral molecules that are modeled using AMBER/GAFF parameters and AM1-BCC charges. Given optimized surface tension coefficients for scaling the surface area term in the nonpolar contribution, most implicit solvent models demonstrate reasonable agreement with extensive explicit solvent simulations (average difference 1.

The shape-shifting quasispecies of RNA: one sequence, many functional folds.

E Unus pluribum, or "Of One, Many", may be at the root of decoding the RNA sequence-structure-function relationship. RNAs embody the large majority of genes in higher eukaryotes and fold in a sequence-directed fashion into three-dimensional structures that perform functions conserved across all cellular life forms, ranging from regulating to executing gene expression. While it is the most important determinant of the RNA structure, the nucleotide sequence is generally not sufficient to specify a unique set of secondary and tertiary interactions due to the highly frustrated nature of RNA folding.

Gd(III)[15-metallacrown-5] recognition of chiral α-amino acid analogues.

Chiral Ln(III)[15-metallacrown-5] complexes with phenyl side chains have been shown to encapsulate aromatic carboxylates reversibly in their hydrophobic cavities. Given the importance of selective guest binding for applications of supramolecular containers in synthesis, separations, and materials design, the affinity of Gd(III)[15-metallacrown(Cu(II), L-pheHA)-5] hosts for a series of chiral carboxylate guests with varying substitutions on the α-carbon (phenylalanine, N-acetyl-phenylalanine, phenyllactate, mandelate, methoxyphenylacetate) has been investigated. Differential binding of S- and R-phenylalanine was revealed by X-ray crystallography, as the S-enantiomer exclusively forms associative hydrogen bonds with oxygen atoms in the metallacrown ring.

Characterizing the resolution and accuracy of a second-generation traveling-wave ion mobility separator for biomolecular ions.

High-accuracy, high-resolution ion mobility measurements enable a vast array of important contemporary applications in biological chemistry. With the recent advent of both new, widely available commercial instrumentation and also new calibration datasets tailored for the aforementioned commercial instrumentation, the possibilities for extending such high performance measurements to a diverse set of applications have never been greater. Here, we assess the performance characteristics of a second-generation traveling-wave ion mobility separator, focusing on those figures of merit that lead to making measurements of collision cross-section having both high precision and high accuracy.

Watching solvent friction impede ultrafast barrier crossings: a direct test of Kramers theory.

A systematic investigation of the solvent's dynamic influence on activated barrier crossings on an electronic ground state is performed using ultrafast two-dimensional infrared chemical exchange spectroscopy. These measurements facilitate a direct comparison with the widely adopted Kramers theory of condensed phase reaction kinetics, and for the first time avoid the significant complication of electronic excitation to probe directly in the time domain a ground electronic state reaction with a well-defined transition state. The picosecond timescale interconversion between two stable isomers of the metal carbonyl complex Co(2)(CO)(8) in a series of linear alkane solvents shows negligible energetic variation with solvent carbon chain length, providing an exclusive probe of the effects of solvent friction.

Palladium (II/IV) catalyzed cyclopropanation reactions: scope and mechanism.

This report describes detailed studies of the scope and mechanism of a new Pd-catalyzed oxidation reaction for the stereospecific conversion of enynes into cyclopropyl ketones. Unlike related Pd(II/0), Au, and Pt-catalyzed cyclopropane-forming reactions, these transformations proceed with net inversion of geometry with respect to the starting alkene. This result, along with other mechanistic data, is consistent with a Pd(II/IV) mechanism in which the key cyclopropane-forming step involves nucleophilic attack of a tethered olefin onto the Pd(IV)-C bond.

An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics.

Incorporating receptor flexibility into molecular docking should improve results for flexible proteins. However, the incorporation of explicit all-atom flexibility with molecular dynamics for the entire protein chain may also introduce significant error and "noise" that could decrease docking accuracy and deteriorate the ability of a scoring function to rank native-like poses. We address this apparent paradox by comparing the success of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38α mitogen-activated protein (MAP) kinase.

Validating CHARMM parameters and exploring charge distribution rules in structure-based drug design.

Using an extensive series of TIBO compounds that are non-nucleoside inhibitors of HIV-1 reverse transcriptase, we have systematically evaluated the quality of recently developed ligand parameters that are consistent with the CHARMM22 force field. Thermodynamic integration simulations for 44 pairs of TIBO compounds achieve a high level of success with an overall average unsigned error (AUE) in the relative binding affinities of 1.3 kcal/mol; however, the accuracy is strongly dependent on the size differential between the substituents sampled as well as the class of functional group.

Synthesis and reactivity of palladium(II) fluoride complexes containing nitrogen-donor ligands.

This article describes the synthesis, characterization, and reactivity of palladium(II) fluoride complexes containing sp(2) and sp(3) nitrogen-containing supporting ligands. Both cis and trans complexes of general structure (N)(N')Pd(II)(R)(F) (R = Ar or CH(3)) as well as cis-(N)(2)Pd(II)(F)(2) are reported. Crystallographic characterization of these molecules has allowed structural comparisons to related phosphine-ligated species.

Insights from coarse-grained Gō models for protein folding and dynamics.

Exploring the landscape of large scale conformational changes such as protein folding at atomistic detail poses a considerable computational challenge. Coarse-grained representations of the peptide chain have therefore been developed and over the last decade have proved extremely valuable. These include topology-based Gō models, which constitute a smooth and funnel-like approximation to the folding landscape.

Multilevel vibrational coherence transfer and wavepacket dynamics probed with multidimensional IR spectroscopy.

Multidimensional infrared (MDIR) spectroscopy of a strongly coupled multilevel vibrational system Mn(2)(CO)(10) (dimanganese decacarbonyl) in cyclohexane solution reveals fully resolved excited vibrational state coherences that exhibit slow 0.25-0.50 ps(-1) decay constants.

Single VS ribozyme molecules reveal dynamic and hierarchical folding toward catalysis.

Non-coding RNAs of complex tertiary structure are involved in numerous aspects of the replication and processing of genetic information in many organisms; however, an understanding of the complex relationship between their structural dynamics and function is only slowly emerging. The Neurospora Varkud Satellite (VS) ribozyme provides a model system to address this relationship. First, it adopts a tertiary structure assembled from common elements, a kissing loop and two three-way junctions.

Effect of conformation and drop properties on surface-enhanced Raman spectroscopy of dried biopolymer drops.

Biofluids are complex solutions consisting of small ions and large biopolymers such as DNA, proteins, or proteoglycans. Biopolymers affect fluid properties but their effect on drop deposition has not been examined. Hyaluronic acid (HA), an important component in synovial fluid, was chosen as a model biopolymer, and examined using surface-enhanced Raman spectroscopy (SERS).

Encapsulation of methylene blue in polyacrylamide nanoparticle platforms protects its photodynamic effectiveness.

The ability to prevent methylene blue (MB), a photosensitizer, from being reduced by plasma reductases will greatly improve its efficacy in photodynamic therapy (PDT) applications. We have developed a delivery approach for PDT by encapsulating MB using nanoparticle platforms (NPs). The 30-nm polyacrylamide-based NPs provide protection for the embedded MB against reduction by diaphorase enzymes.

Conformation dependence of the CalphaDalpha stretch mode in peptides. 1. Isolated alanine peptide structures.

Ab initio normal mode calculations have been performed on isolated alanine di- through octa-(i.e., blocked) peptides in uniform alphaR, beta, and polyproline II conformations to determine how the CalphaDalpha stretch mode, which has been proposed as a possible determinant of the varphi,psi conformation at the Calpha atom (Mirkin, N.