The Chirality of Isotopomers of Glycine Compared using Next-Generation QTAIM

The effect of the presence of a deuterium (D) or tritium (T) isotope bonded to the alpha carbon of glycine is determined without the need to apply external forces e.g. electric fields or using normal mode analysis. Isotopic effects were accounted for using the mass-dependent diagonal Born-Oppenheimer energy correction (DBOC) at the CCSD level of theory. We calculated the stress tensor trajectories of the dominant C-N bond within next generation quantum theory of atoms in molecules (NG-QTAIM). S-character chirality was discovered using the stress tensor trajectories, instead of the Cahn–Ingold–Prelog (CIP) rules, for ordinary glycine. The S-character chirality was preserved after the substitution of the H on the alpha carbon for a D isotope but transformed to R-character chirality after replacement with the T isotope. This reversal of the chirality depending on the presence of a single D or T isotope bound to the alpha carbon adds to the debate on the nature of the extraterrestrial origins of chirality in simple amino acids. We demonstrate that NG-QTAIM is a promising tool for understanding isotopic induced electronic charge density changes, useful in analysis of infrared (IR) or circular dichroism (CD) spectra explaining changes in mode couplings and bands intensities or sign.

Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition

Conformations of Cα backbones in X-ray structures of most organophosphate (OP)-inhibited human acetylcholinesterases (hAChEs) have been previously shown to be similar to that of the native hAChE. One of the exceptions is the structure of the diethylphosphoryl-hAChE conjugate, where stabilization of a large ethoxy group into the acyl pocket (AP) of hAChE-triggered notable loop distortions and consequential dissociation of the hAChE homodimer. Recently, six X-ray structures of hAChE conjugated with large OP nerve agents of the A-type, Novichoks, have been deposited to PDB. In this study we analyzed backbone conformation shifts in those structures, as well as in OP-hAChE conjugates formed by Paraoxon, Soman, Tabun, and VX. A Java-based pairwise alpha carbon comparison tool (PACCT 3) was used for analysis. Surprisingly, despite the snug fit of large substituents on phosphorus, inside Novichok-conjugated hAChEs only minor conformational changes were detected in their backbones. Small magnitudes of observed changes were due to a 1.2–2.4 Å shift of the entire conjugated OP away from the AP. It thus appears that the small AP of AChEs can accommodate, without distortion, substituents of the size of ethoxy or butyryl groups, provided that conjugated OP is “pulled” away from the AP. This observation has practical consequences in the structure-based design of nucleophilic reactivation antidotes as well as in the definition of the AChE specificity that relies on the size of its AP.

Gaussian Network Model Revisited: Effects of Mutation and Ligand Binding on Protein Behavior

The coarse-grained Gaussian Network model, GNM, considers only the alpha carbons of the folded protein. Therefore it is not directly applicable to the study of mutation or ligand binding problems where atomic detail is required. This shortcoming is improved by including the local effect of heavy atoms in the neighborhood of each alpha carbon into the Kirchoff Adjacency Matrix. The presence of other atoms in the coordination shell of each alpha carbon diminishes the magnitude of fluctuations of that alpha carbon. But more importantly, it changes the graph-like connectivity structure, i.e., the Kirchoff Adjacency Matrix of the whole system which introduces amino acid specific and position specific information into the classical coarse-grained GNM which was originally modelled in analogy with phantom network theory of rubber elasticity. With this modification, it is now possible to make predictions on the effects of mutation and ligand binding on residue fluctuations and their pair-correlations. We refer to the new model as all-atom GNM. Using examples from published data we show that the all-atom GNM applied to in silico mutated proteins and to their laboratory mutated structures gives similar results. Thus, loss and gain of correlations, which may be related to loss and gain of function, may be studied by using simple in silico mutations only.

Exact solution of two-potential system under same range approximation and its implication

In this paper, exact analytical expressions for the Jost solution and Jost function are derived for motion in the nuclear Manning–Rosen plus the Hulthén potential to study both the bound and scattering state observables. The proton-deuteron and alpha-carbon systems are studied to judge the merit of our approach. Our results are found in reasonable agreement with experimental data.

Current Advancements in Sactipeptide Natural Products

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a growing class of natural products that benefited from genome sequencing technology in the past two decades. RiPPs are widely distributed in nature and show diverse chemical structures and rich biological activities. Despite the various structural characteristic of RiPPs, they follow a common biosynthetic logic: a precursor peptide containing an N-terminal leader peptide and a C-terminal core peptide; in some cases,a follower peptide is after the core peptide. The precursor peptide undergoes a series of modification, transport, and cleavage steps to form a mature natural product with specific activities. Sactipeptides (Sulfur-to-alpha carbon thioether cross-linked peptides) belong to RiPPs that show various biological activities such as antibacterial, spermicidal and hemolytic properties. Their common hallmark is an intramolecular thioether bond that crosslinks the sulfur atom of a cysteine residue to the α-carbon of an acceptor amino acid, which is catalyzed by a rSAM enzyme. This review summarizes recent achievements concerning the discovery, distribution, structural elucidation, biosynthesis and application prospects of sactipeptides.

Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior

Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l-Glu or l-Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous l-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport l-Gln.

Deciphering Aspartyl Peptide Sweeteners Using the Ultimate Molecular Theory of Sweet Taste

More than thirty years ago, I proposed a theory about sweet and bitter molecules’ recognition by protein helical structures. Unfortunately the papers<br>could not go to public platform until now. The sweet and bitter taste theory is updated and presented in separated papers. 1,2 Under the guidance of the sweet<br>receptor helix recognition theory 1, aspartyl/aminomalonyl peptide sweeteners are deciphered. Here it demonstrates that, this series of sweeteners has a<br>hydrogen-bond type hydrogen donor - hydrogen acceptor DH-B moiety and their DH-B is very special. Their B of the DH-B moiety is an oxygen of the carboxylic<br>group, which is widely accepted one. The DH of the DH-B moiety however is the NH of the aspartyl/aminomalonyl peptide, which is a selection for the first time to<br>the best of my knowledge. Even more unusual, their dynamic action acts through<br>the hydrogen on alpha carbon of aspartyl/aminomalonyl group. The receptor main and side grooves have different space characteristics in accepting sweet<br>molecules’ groups, which is elaborated in this paper. This unprecedented elucidation well explains the aspartyl/aminomalonyl peptide sweeteners’<br>phenomenon and, in return, strongly supports this sweet receptor helix recognition theory.

Deciphering Aspartyl Peptide Sweeteners Using the Ultimate Molecular Theory of Sweet Taste

More than thirty years ago, I proposed a theory about sweet and bitter molecules’ recognition by protein helical structures. Unfortunately the papers<br>could not go to public platform until now. The sweet and bitter taste theory is updated and presented in separated papers. 1,2 Under the guidance of the sweet<br>receptor helix recognition theory 1, aspartyl/aminomalonyl peptide sweeteners are deciphered. Here it demonstrates that, this series of sweeteners has a<br>hydrogen-bond type hydrogen donor - hydrogen acceptor DH-B moiety and their DH-B is very special. Their B of the DH-B moiety is an oxygen of the carboxylic<br>group, which is widely accepted one. The DH of the DH-B moiety however is the NH of the aspartyl/aminomalonyl peptide, which is a selection for the first time to<br>the best of my knowledge. Even more unusual, their dynamic action acts through<br>the hydrogen on alpha carbon of aspartyl/aminomalonyl group. The receptor main and side grooves have different space characteristics in accepting sweet<br>molecules’ groups, which is elaborated in this paper. This unprecedented elucidation well explains the aspartyl/aminomalonyl peptide sweeteners’<br>phenomenon and, in return, strongly supports this sweet receptor helix recognition theory.

DeepPSC (protein structure camera): computer vision-based protein backbone structure reconstruction from alpha carbon trace as a case study

Deep learning has been increasingly used in protein tertiary structure prediction, a major goal in life science. However, all the algorithms developed so far mostly use protein sequences as input, whereas the vast amount of protein tertiary structure information available in the Protein Data Bank (PDB) database remains largely unused, because of the inherent complexity of 3D data computation. In this study, we propose Protein Structure Camera (PSC) as an approach to convert protein structures into images. As a case study, we developed a deep learning method incorporating PSC (DeepPSC) to reconstruct protein backbone structures from alpha carbon traces. DeepPSC outperformed all the methods currently available for this task. This PSC approach provides a useful tool for protein structure representation, and for the application of deep learning in protein structure prediction and protein engineering.