Systematic QM Region Construction in QM/MM Calculations Based on Uncertainty Quantification

While QM/MM studies of enzymatic reactions are widely used in computational chemistry, the results of such studies are subject to numerous sources of uncertainty, and the effect of different choices by the simulation scientist that are required when setting up QM/MM calculations is often unclear. In particular, the selection of the QM region is crucial for obtaining accurate and reliable results. Simply including amino acids by their distance to the active site is mostly not sufficient as necessary residues are missing or unimportant residues are included without evidence. Here, we take a first step towards quantifying uncertainties in QM/MM calculations by assessing the sensitivity of QM/MM reaction energies with respect to variations of the MM point charges. We show that such a point charge variation analysis (PCVA) can be employed to judge the accuracy of QM/MM reaction energies obtained with a selected QM region, and devise a protocol to systematically construct QM regions that minimize this uncertainty. We apply such a PCVA to the example of catechol \textit{O}-methyltransferase, and demonstrate that it provides a simple and reliable approach for the construction of the QM region. Our PCVA-based scheme is computationally efficient and requires only calculations for a system with a minimal QM region. Our work highlights the promise of applying methods of uncertainty quantification in computational chemistry.

Adaptation to the Risks of Digitalization: New Survival Trends for States in a Multipolar World

The purpose is to study the new survival trends for states in a multipolar world, determine the successfulness of adaptation to the digitalization of different growth poles, and develop the applied recommendations to improve the practice of adaptation to the risks of digitalization of these growth poles. Design/methodology/approach. The authors use the methods of economic statistics: variation analysis, trend analysis, correlation analysis, and regression analysis. Findings. The commonness of strategies of adaptation to the risks of digitalization for different poles of the world economy is substantiated, and two universal mechanisms—talent management and development of science—are found. The originality of this research is due to the consideration of digitalization from a new view—from the positions of setting states at the brink of survival due to the aggressive digital competition and high complexity of ensuring global competition in a quickly changing digital landscape. The uniqueness of this research is due to taking into account the specific features in a multipolar world. The practical implementation of the offered recommendations opens future perspectives for more successful survival trends in a multipolar world and the improvement of their adaptation to risks digitalization by 69.91% in G7 countries (on average) and by 88.40% in BRICS countries (on average).

Dormant spores sense amino acids through the B subunits of their germination receptors

Bacteria from the orders Bacillales and Clostridiales differentiate into stress-resistant spores that can remain dormant for years, yet rapidly germinate upon nutrient sensing. How spores monitor nutrients is poorly understood but in most cases requires putative membrane receptors. The prototypical receptor from Bacillus subtilis consists of three proteins (GerAA, GerAB, GerAC) required for germination in response to L-alanine. GerAB belongs to the Amino Acid-Polyamine-Organocation superfamily of transporters. Using evolutionary co-variation analysis, we provide evidence that GerAB adopts a structure similar to an L-alanine transporter from this superfamily. We show that mutations in gerAB predicted to disrupt the ligand-binding pocket impair germination, while mutations predicted to function in L-alanine recognition enable spores to respond to L-leucine or L-serine. Finally, substitutions of bulkier residues at these positions cause constitutive germination. These data suggest that GerAB is the L-alanine sensor and that B subunits in this broadly conserved family function in nutrient detection.