Trioxane-based MS-cleavable cross-linking mass spectrometry for profiling multimeric interactions of cellular networks.

Cross-linking mass spectrometry (XL-MS) is a powerful technology for mapping protein-protein interactions (PPIs) at the systems level. While bivalent cross-links are effective for defining protein interactions and structures, multivalent cross-links offer enhanced spatial resolution to facilitate characterization of heterogeneous protein complexes. However, their identification remains challenging due to fragmentation complexity and the vast expansion of database search space.

Molecular mechanism of substrate transport by human peroxisomal ABCD3.

Peroxisomes are eukaryotic oxidative organelles involved in numerous metabolic functions that include fatty acid oxidation, bile acid synthesis, and detoxification of reactive oxygen species. ATP-binding cassette transporters of the D subfamily (ABCD1-3) mediate the import of CoA thioesters of fatty acids into the peroxisome. ABCD3, the most abundant of these transporters in the peroxisomal membrane, facilitates the transport of a broad spectrum of substrates including branched-chain fatty acids, very long-chain fatty acids, bile salt intermediates, and dicarboxylic acids.

Structure and inhibition mechanisms of Mycobacterium tuberculosis essential transporter efflux protein A.

A broad chemical genetic screen in Mycobacterium tuberculosis (Mtb) identified compounds (BRD-8000.3 and BRD-9327) that inhibit the essential efflux pump EfpA. To understand the mechanisms of inhibition, we determined the structures of EfpA with these inhibitors bound at 2.

Structural basis of disease mutation and substrate recognition by the human SLC2A9 transporter.

Urate provides ~50% of the reducing potential in human and primate plasma which is key to detoxifying reactive oxygen by-products of cellular metabolism. Urate is the endpoint of purine metabolism in primates, and its concentration in plasma is a balance between excretion from kidney and intestine, and subsequent reabsorption in and through cells of kidney proximal tubules to maintain a regulated concentration in plasma. SLC2A9 is the primary transporter that returns urate from the basolateral side of kidney tubule cells back to plasma.

Directed Evolution's Selective Use of Quantum Tunneling in Designed Enzymes─A Combined Theoretical and Experimental Study.

Natural enzymes are powerful catalysts, reducing the apparent activation energy for reactions and enabling chemistry to proceed as much as 10 times faster than the corresponding solution reaction. It has been suggested for some time that, in some cases, quantum tunneling can contribute to this rate enhancement by offering pathways through a barrier inaccessible to activated events. A central question of interest to both physical chemists and biochemists is the extent to which evolution introduces mechanisms below the barrier, or tunneling mechanisms.

Structure and inhibition mechanisms of essential transporter efflux protein A.

A broad chemical genetics screen in to identify inhibitors of established or previously untapped targets for therapeutic development yielded compounds (BRD-8000.3 and BRD-9327) that inhibit the essential efflux pump EfpA. To understand the mechanisms of inhibition by these compounds, we determined the structures of EfpA with inhibitors bound at 2.

Transition Path Sampling Study of Engineered Enzymes That Catalyze the Morita-Baylis-Hillman Reaction: Why Is Enzyme Design so Difficult?

It is hoped that artificial enzymes designed in laboratories can be efficient alternatives to chemical catalysts that have been used to synthesize organic molecules. However, the design of artificial enzymes is challenging and requires a detailed molecular-level analysis to understand the mechanism they promote in order to design efficient variants. In this study, we computationally investigate the mechanism of proficient Morita-Baylis-Hillman enzymes developed using a combination of computational design and directed evolution.

Connecting Conformational Motions to Rapid Dynamics in Human Purine Nucleoside Phosphorylase.

The influence of protein motions on enzyme catalysis remains a topic of active discussion. Protein motions occur across a variety of time scales, from vibrational fluctuations in femtoseconds, to collective motions in milliseconds. There have been numerous studies that show conformational motions may assist in catalysis, protein folding, and substrate specificity.

Static polarizabilities within the generalized Kohn-Sham semicanonical projected random phase approximation (GKS-spRPA).

An analytical implementation of static dipole polarizabilities within the generalized Kohn-Sham semicanonical projected random phase approximation (GKS-spRPA) method for spin-restricted closed-shell and spin-unrestricted open-shell references is presented. General second-order analytical derivatives of the GKS-spRPA energy functional are derived using a Lagrangian approach. By resolution-of-the-identity and complex frequency integration methods, an asymptotic O(N⁡log(N)) scaling of operation count and O(N) scaling of storage is realized, i.

Transition Path Sampling Based Calculations of Free Energies for Enzymatic Reactions: The Case of Human Methionine Adenosyl Transferase and Adenosine Deaminase.

Transition path sampling (TPS) is widely used for the calculations of reaction rates, transition state structures, and reaction coordinates of condensed phase systems. Here we discuss a scheme for the calculation of free energies using the ensemble of TPS reactive trajectories in combination with a window-based sampling technique for enzyme-catalyzed reactions. We calculate the free energy profiles of the reactions catalyzed by the human methionine -adenosyltransferase (MAT2A) enzyme and the adenosine deaminase (ADA) enzyme to assess the accuracy of this method.

High-Resolution X-ray Photoelectron Spectroscopy of Organometallic (CHSiMe)Ln and [(CHSiMe)Ln] Complexes (Ln = Sm, Eu, Gd, Tb).

The capacity of X-ray photoelectron spectroscopy (XPS) to provide information on the electronic structure of molecular organometallic complexes of Ln(II) ions (Ln = lanthanide) has been examined for the first time. XPS spectra were obtained on the air-sensitive molecular trivalent 4f Cp'Ln complexes (Ln = Sm, Eu, Gd, Tb; Cp' = CHSiMe) and compared to those of the highly reactive divalent complexes, [K(crypt)][Cp'Ln] (crypt = 2.2.

Exploring the Solvation of Acetic Acid in Water Using Liquid Jet X-ray Photoelectron Spectroscopy and Core Level Electron Binding Energy Calculations.

Liquid jet X-ray photoelectron spectroscopy was used to investigate changes in the local electronic structure of acetic acid in the bulk of aqueous solutions induced by solvation effects. These effects manifest themselves as shifts in the difference in the carbon 1s binding energy (ΔBE) between the methyl and carboxyl carbons of acetic acid. Furthermore, molecular dynamics simulations, coupled with correlated electronic structure calculations of the first solvation sphere, provide insight into the number of water molecules directly interacting with the carboxyl group that are required to match the ΔBE from the photoelectron spectroscopy experiments.

TURBOMOLE: Modular program suite for ab initio quantum-chemical and condensed-matter simulations.

TURBOMOLE is a collaborative, multi-national software development project aiming to provide highly efficient and stable computational tools for quantum chemical simulations of molecules, clusters, periodic systems, and solutions. The TURBOMOLE software suite is optimized for widely available, inexpensive, and resource-efficient hardware such as multi-core workstations and small computer clusters. TURBOMOLE specializes in electronic structure methods with outstanding accuracy-cost ratio, such as density functional theory including local hybrids and the random phase approximation (RPA), GW-Bethe-Salpeter methods, second-order Møller-Plesset theory, and explicitly correlated coupled-cluster methods.

Formation of the End-on Bound Lanthanide Dinitrogen Complexes [(RN)Ln-N═N-Ln(NR)] from Divalent [(RN)Ln] Salts (R = SiMe).

Lanthanide-based dinitrogen reduction chemistry has been expanded by the discovery of the first end-on Ln(μ-η:η-N) complexes, whose synthesis and reactivity help explain the reduction of N by the combination of trivalent Ln(NR) complexes (R = SiMe) and potassium. The formation of end-on versus the more common side-on Ln(μ-η:η-N) complexes is possible by using recently discovered Ln(II) complexes ligated by three NR amide ligands (R = SiMe). The isolated Ln(II) tris(amide) complex [K(crypt)][Tb(NR)] (crypt = 2.

Synthesis, Structure, and Magnetism of Tris(amide) [Ln{N(SiMe ) } ] Complexes of the Non-traditional +2 Lanthanide Ions.

A new series of Ln complexes has been synthesized that overturns two previous generalizations in rare-earth metal reduction chemistry: that amide ligands do not form isolable complexes of the highly reducing non-traditional Ln ions, and that yttrium is a good model for the late lanthanides in these reductive reactions. Reduction of Ln(NR ) (R=SiMe ) complexes in THF under Ar with M=K or Rb in the presence of 2.2.

Random-Phase Approximation Methods.

Random-phase approximation (RPA) methods are rapidly emerging as cost-effective validation tools for semilocal density functional computations. We present the theoretical background of RPA in an intuitive rather than formal fashion, focusing on the physical picture of screening and simple diagrammatic analysis. A new decomposition of the RPA correlation energy into plasmonic modes leads to an appealing visualization of electron correlation in terms of charge density fluctuations.

Noble gas encapsulation into carbon nanotubes: predictions from analytical model and DFT studies.

The energetics for the interaction of the noble gas atoms with the carbon nanotubes (CNTs) are investigated using an analytical model and density functional theory calculations. Encapsulation of the noble gas atoms, He, Ne, Ar, Kr, and Xe into CNTs of various chiralities is studied in detail using an analytical model, developed earlier by Hill and co-workers. The constrained motion of the noble gas atoms along the axes of the CNTs as well as the off-axis motion are discussed.