DOCKING PROBLEMS: PROTEIN-LIGAND LOW ENERGY MINIMA ANALYSIS-

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Accuracy comparison of several common implicit solvent models and their implementations in the context of protein-ligand binding.

In this study several commonly used implicit solvent models are compared with respect to their accuracy of estimating solvation energies of small molecules and proteins, as well as desolvation penalty in protein-ligand binding. The test set consists of 19 small proteins, 104 small molecules, and 15 protein-ligand complexes. We compared predicted hydration energies of small molecules with their experimental values; the results of the solvation and desolvation energy calculations for small molecules, proteins and protein-ligand complexes in water were also compared with Thermodynamic Integration calculations based on TIP3P water model and Amber12 force field. The following implicit solvent (water) models considered here are: PCM (Polarized Continuum Model implemented in DISOLV and MCBHSOLV programs), GB (Generalized Born method implemented in DISOLV program, S-GB, and GBNSR6 stand-alone version), COSMO (COnductor-like Screening Model implemented in the DISOLV program and the MOPAC package) and the Poisson-Boltzmann model (implemented in the APBS program). Different parameterizations of the molecules were examined: we compared MMFF94 force field, Amber12 force field and the quantum-chemical semi-empirical PM7 method implemented in the MOPAC package. For small molecules, all of the implicit solvent models tested here yield high correlation coefficients (0.87-0.93) between the calculated solvation energies and the experimental values of hydration energies. For small molecules high correlation (0.82-0.97) with the explicit solvent energies is seen as well. On the other hand, estimated protein solvation energies and protein-ligand binding desolvation energies show substantial discrepancy (up to 10kcal/mol) with the explicit solvent reference. The correlation of polar protein solvation energies and protein-ligand desolvation energies with the corresponding explicit solvent results is 0.65-0.99 and 0.76-0.96 respectively, though this difference in correlations is caused more by different parameterization and less by methods and indicates the need for further improvement of implicit solvent models parameterization. Within the same parameterization, various implicit methods give practically the same correlation with results obtained in explicit solvent model for ligands and proteins: e.g. correlation values of polar ligand solvation energies and the corresponding energies in the frame of explicit solvent were 0.953-0.966 for the APBS program, the GBNSR6 program and all models used in the DISOLV program. The DISOLV program proved to be on a par with the other used programs in the case of proteins and ligands solvation energy calculation. However, the solution of the Poisson-Boltzmann equation (APBS program) and Generalized Born method (implemented in the GBNSR6 program) proved to be the most accurate in calculating the desolvation energies of complexes

Tyumen District in 1920s: Settlement Numbers and Development Features

The subject of this study is the rural settlements of the Tyumen district in the first quarter of the 20th century. It is noted that during this period, the Tyumen district was situated at the heart of the Tyumen region, ranking first in terms of population size (44,545 people) and the area of territory covered (5.4 thousand square kilometers). The paper examines changes in the number and typology of settlements within the Tyumen district through the lens of its rural localities. It has been established that the district’s settlement network consisted of 177 localities, falling into 11 types, with villages making up a significant proportion — over 50%. This fact indicates that in long-settled regions, settlement networks have existed in virtually unchanged forms despite various external and internal factors. Fifteen villages were identified as creating the framework of the Tyumen district’s settlement network, demonstrating resilience and successfully adapting to new conditions. For instance, data from 1912 and 1926 show that population numbers in these localities were growing, especially in those settlements occupying advantageous (central) positions within the existing network. Many villages in the Tyumen district attained this status during the Soviet period, even though at the beginning of the 20th century they were mere villages. Successful new connections between settlements were facilitated by transportation factors (the presence of railways, tract roads, and a navigable water artery — the Tura River)