Protein-Ligand Binding Free-Energy Calculations with ARROW─A Purely First-Principles Parameterized Polarizable Force Field.

Protein-ligand binding free-energy calculations using molecular dynamics (MD) simulations have emerged as a powerful tool for in silico drug design. Here, we present results obtained with the ARROW force field (FF)─a multipolar polarizable and physics-based model with all parameters fitted entirely to high-level ab initio quantum mechanical (QM) calculations. ARROW has already proven its ability to determine solvation free energy of arbitrary neutral compounds with unprecedented accuracy. The ARROW FF parameterization is now extended to include coverage of all amino acids including charged groups, allowing molecular simulations of a series of protein-ligand systems and prediction of their relative binding free energies. We ensure adequate sampling by applying a novel technique that is based on coupling the Hamiltonian Replica exchange (HREX) with a conformation reservoir generated via potential softening and nonequilibrium MD. ARROW provides predictions with near chemical accuracy (mean absolute error of ∼0.5 kcal/mol) for two of the three protein systems studied here (MCL1 and Thrombin). The third protein system (CDK2) reveals the difficulty in accurately describing dimer interaction energies involving polar and charged species. Overall, for all of the three protein systems studied here, ARROW FF predicts relative binding free energies of ligands with a similar accuracy level as leading nonpolarizable force fields.

Accurate determination of solvation free energies of neutral organic compounds from first principles.

The main goal of molecular simulation is to accurately predict experimental observables of molecular systems. Another long-standing goal is to devise models for arbitrary neutral organic molecules with little or no reliance on experimental data. While separately these goals have been met to various degrees, for an arbitrary system of molecules they have not been achieved simultaneously. For biophysical ensembles that exist at room temperature and pressure, and where the entropic contributions are on par with interaction strengths, it is the free energies that are both most important and most difficult to predict. We compute the free energies of solvation for a diverse set of neutral organic compounds using a polarizable force field fitted entirely to ab initio calculations. The mean absolute errors (MAE) of hydration, cyclohexane solvation, and corresponding partition coefficients are 0.2 kcal/mol, 0.3 kcal/mol and 0.22 log units, i.e. within chemical accuracy. The model (ARROW FF) is multipolar, polarizable, and its accompanying simulation stack includes nuclear quantum effects (NQE). The simulation tools' computational efficiency is on a par with current state-of-the-art packages. The construction of a wide-coverage molecular modelling toolset from first principles, together with its excellent predictive ability in the liquid phase is a major advance in biomolecular simulation.

Materials extrusion-inspired engineering reflection of social pressure-induced environmental impact on academy community well-being.

BACKGROUND: Existing issues with student mental health are the sources of ongoing violation of academic and educational integrity in learning and instructional dynamics in all educational institutions worldwide. OBJECTIVE: This didactical paper addresses the practical case of educational integrity violations induced by student mental illness. It presents a thought-provoking unified viewpoint of the existence of a non-obvious geometric analogy between the irreversible psycho-social process of mental disorder growth and the irreversible pressure forming-induced deformation process of materials extrusion through an angular domain. METHODS: This paper uses the method of geometric analogy between the dynamics of social irreversible processes in human society and technical irreversible processes in materials extrusion. RESULTS: The novel analogy between the loss of elliptical shape of an initial circular material element within pressure-extruded material and the development of student mental inadequacy during intensive university education was firstly studied and analyzed in detail. CONCLUSIONS: The author-proposed original socio-technical cross-disciplinary analogy improves and broadens student understanding of nonlinear dynamics both in the technical processes of macroscopic rotation formation in pressure-formed material and in the bio-social processes of psycho-neurological pathology development within a learner's mind.