Helical Content Correlations and Hydration Structures of the Folding Ensemble of the B Domain of Protein A.

The B domain of protein A (BdpA), a small three-helix bundle, folds on a time scale of a few microseconds with heterogeneous native and unfolded states. It is widely used as a model for understanding protein folding mechanisms. In this work, we use structure-based models (SBMs) and atomistic simulations to comprehensively investigate how BdpA folding is associated with the formation of its secondary structure. The energy landscape visualization method (ELViM) was used to characterize the pathways that connect the folded and unfolded states of BdpA as well as the sets of structures displaying specific ellipticity patterns. We show that the native state conformational diversity is due mainly to the conformational variability of helix I. Helices I, II, and III occur in a weakly correlated manner, with Spearman's rank correlation coefficients of 0.1539 (I and II), 0.1259 (I and III), and 0.2561 (II and III). These results, therefore, suggest the highest cooperativity between helices II and III. Our results allow the clustering of partially folded structures of folding of the B domain of protein A on the basis of its secondary structure, paving the way to an understanding of environmental factors in the relative stability of the basins of the folding ensemble, which are illustrated by the structural dependency of the protein hydration structures, as computed with minimum-distance distribution functions.

Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study.

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.

Development of technologies applied to the biodegradation of warfare nerve agents: Theoretical evidence for asymmetric homogeneous catalysis.

Organophosphorus compounds have been widely employed to the development of warfare nerve agents and pesticides, resulting in a huge number of people intoxicated annually, being a serious problem of public health. Efforts worldwide have been done in order to design new technologies that are capable of combating or even reversing the poisoning caused by these OP nerve agents. In this line, the bioremediation arises as a promising and efficient alternative for this purpose. As an example of degrading enzymes, there is the organophosphate-degrading (OpdA) enzyme from Agrobacterium radiobacter, which has been quite investigated experimentally due to its high performance in the degradation of neurotoxic nerve agents. This work aims to look into the structural and electronic details that govern the interaction modes of these compounds in the OpdA active site, with the posterior hydrolysis reaction prediction. Our findings have brought about data about the OpdA performance towards different nerve agents, and among them, we may realize that the degradation efficiency strongly depends on the nerve agent structure and its stereochemistry, being in this case the compound Tabun the one more effectively hydrolyzed. By means of the chemical bonds (AIM) and orbitals (FERMO) analysis, it is suggested that the initial reactivity of the OP nerve agents in the OpdA active site does not necessarily dictate the reactivity and interaction modes over the reaction coordinate.

Asymmetric biodegradation of the nerve agents Sarin and VX by human dUTPase: chemometrics, molecular docking and hybrid QM/MM calculations.

Organophosphorus compounds (OP) nerve agents are among the most toxic chemical substances known. Their toxicity is due to their ability to bind to acetylcholinesterase. Currently, some enzymes, such as phosphotriesterase, human serum paraoxonase 1 and diisopropyl fluorophosphatase, capable of degrading OP, have been characterized. Regarding the importance of bioremediation methods for detoxication of OP, this work aims to study the interaction modes between the human human deoxyuridine triphosphate nucleotidohydrolase (dUTPase) and Sarin and VX, considering their Rp and Sp enantiomers, to evaluate the asymmetric catalysis of those compounds. In previous work, this enzyme has shown good potential to degrade phosphotriesters, and based on this characteristic, we have applied the human dUTPase to the OP degradation. Molecular docking, chemometrics and mixed quantum and molecular mechanics calculations have been employed, showing a good interaction between dUTPase and OP. Two possible reaction mechanisms were tested, and according to our theoretical results, the catalytic degradation of OP by dUTPase can take place via both mechanisms, beyond being stereoselective, that is, dUTPase cleaves one enantiomer preferentially in relation to other. Chemometric techniques provided excellent assistance for performing this theoretical investigation. The dUTPase study shows importance by the fact of it being a human enzyme. Communicated by Ramaswamy H. Sarma.