Property distributions: differences between drugs,natural products,and molecules from combinatorial chemistry

The differences between three different compound classes, natural products, molecules from combinatorial synthesis, and drug molecules, were investigated. The major structural differences between natural and combinatorial compounds originate mainly from properties introduced to make combinatorial synthesis more efficient. These include the number of chiral centers, the prevalence of aromatic rings, the introduction of complex ring systems, and the degree of the saturation of the molecule as well as the number and ratios of different heteroatoms. As drug molecules derive from both natural and synthetic sources, they cover a joint area in property space of natural and combinatorial compounds. A PCA-based scheme is presented that differentiates the three classes of compounds. It is suggested that by mimicking certain distribution properties of natural compounds, combinatorial products might be made that are substantially more diverse and have greater biological relevance.     

Tuning a High Transmission Ion Guide to Prevent Gas-Phase Proton Exchange During H/D Exchange MS Analysis

Hydrogen/deuterium exchange (HDX) mass spectrometry (MS) for protein structural analysis has been adopted for many purposes, including biopharmaceutical development. One of the benefits of examining amide proton exchange by mass spectrometry is that it can readily resolve different exchange regimes, as evidenced by either binomial or bimodal isotope patterns. By careful analysis of the isotope pattern during exchange, more insight can be obtained on protein behavior in solution. However, one must be sure that any observed bimodal isotope patterns are not artifacts of analysis and are reflective of the true behavior in solution. Sample carryover and certain stationary phases are known as potential sources of bimodal artifacts. Here, we describe an additional undocumented source of deuterium loss resulting in artificial bimodal patterns for certain highly charged peptides. We demonstrate that this phenomenon is predominantly due to gas-phase proton exchange between peptides and bulk solvent within the initial stages of high-transmission conjoined ion guides. Minor adjustments of the ion guide settings, as reported here, eliminate the phenomenon without sacrificing signal intensity. Such gas-phase deuterium loss should be appreciated for all HDX-MS studies using such ion optics, even for routine studies not focused on interpreting bimodal spectra.

Open image in new window

Graphical Abstract ?

     

Transient and First Passage Time Distributions of First- and Second-order Multi-regime Markov Fluid Queues via ME-fication

We propose a numerical method to obtain the transient and first passage time distributions of first- and second-order Multi-Regime Markov Fluid Queues (MRMFQ). The method relies on the observation that these transient measures can be computed via the stationary analysis of an auxiliary MRMFQ. This auxiliary MRMFQ is constructed from the original one, using sample path arguments, and has a larger cardinality stemming from the need to keep track of time. The conventional method to approximately model the deterministic time horizon is Erlangization. As an alternative, we propose the so-called ME-fication technique, in which a Concentrated Matrix Exponential (CME) distribution replaces the Erlang distribution for approximating deterministic time horizons. ME-fication results in much lower state-space dimensionalities for the auxiliary MRMFQ than would be with Erlangization. Numerical results are presented to validate the effectiveness of ME-fication along with the proposed numerical method.

     

Structure-based design of supercharged, highly thermoresistant antibodies

Mutation of surface residues to charged amino acids increases resistance to aggregation and can enable reversible unfolding. We have developed a protocol using the Rosetta computational design package that "supercharges" proteins while considering the energetic implications of each mutation. Using?a homology model, a single-chain variable fragment antibody was designed that has a markedly enhanced resistance to thermal inactivation and displays an unanticipated ≈30-fold improvement in affinity. Such supercharged antibodies should prove useful for assays in resource-limited settings and for developing reagents with improved shelf lives.     

Universal flow-driven conical emission in ultrarelativistic heavy-ion collisions

The double-peak structure observed in soft-hard hadron correlations is commonly interpreted as a signature for a Mach cone generated by a supersonic jet interacting with the hot and dense medium created in ultrarelativistic heavy-ion collisions. We show that it can also arise due to averaging over many jet events in a transversally expanding background. We find that the jet-induced away-side yield does not depend on the details of the energy-momentum deposition in the plasma, the jet velocity, or the system size. Our claim can be experimentally tested by comparing soft-hard correlations induced by heavy-flavor jets with those generated by light-flavor jets.     

Properties of Sizeable [n]Cycloparaphenylenes as Molecular Models of Single‐Wall Carbon Nanotubes Elucidated by Raman Spectroscopy: Structural and Electron‐Transfer Responses under Mechanical Stress

[n]Cycloparaphenylenes behave as molecular templates of “perfectly chemically defined” single‐wall carbon nanotubes. These [n]CPP molecules have electronic, mechanical, and chemical properties in size correspondence with their giant congeners. Under mechanical stress, they form charge‐transfer salts, or complexes with fullerene, by one‐electron concave–convex electron transfer.     

Charge shift bonding concept in radical π-dimers

We show that pancake bonding in radical π-dimers display features of charge shift (CS) bonding. While the CS bonding concept has been developed to interpret the unusual aspects of σ-bonds around centers with a large number of lone pairs, such as F(2) and HOOH, we find a similar role played by the nonbonding or slightly bonding π-electron pairs in π-stacking radical dimers. Arguments and computational evidence indicate that the CS bonding concept developed by Shaik and Hiberty et al. captures essential features of the intermolecular bonding in radical π-dimers in which the overlap of the two radical centered singly occupied molecular orbitals (SOMOs) play a crucial role. By using the tetracyanoethylene anion dimer, [TCNE](2)(2-), as a model, we show that compared to CAS(2,2) calculations, significant binding contributions are recovered in the calculations simply by including selected intrapair excitations of the SOMO-SOMO bonding orbitals and the nonbonding π-orbitals. This observation is the basis for the analogy of chemical bonding between pancake bonded radical π-dimers and other charge shift bonded molecules, such as F(2). By extending the CS bonding concept to a new class of molecules, we find a novel application of the lone pair bond weakening effect (LPBWE) in which the doubly occupied π-orbitals play the role of lone pairs.