An exploration of machine learning models for the determination of reaction coordinates associated with conformational transitions.

Determining collective variables (CVs) for conformational transitions is crucial to understanding their dynamics and targeting them in enhanced sampling simulations. Often, CVs are proposed based on intuition or prior knowledge of a system. However, the problem of systematically determining a proper reaction coordinate (RC) for a specific process in terms of a set of putative CVs can be achieved using committor analysis (CA). Identifying essential degrees of freedom that govern such transitions using CA remains elusive because of the high dimensionality of the conformational space. Various schemes exist to leverage the power of machine learning (ML) to extract an RC from CA. Here, we extend these studies and compare the ability of 17 different ML schemes to identify accurate RCs associated with conformational transitions. We tested these methods on an alanine dipeptide in vacuum and on a sarcosine dipeptoid in an implicit solvent. Our comparison revealed that the light gradient boosting machine method outperforms other methods. In order to extract key features from the models, we employed Shapley Additive exPlanations analysis and compared its interpretation with the "feature importance" approach. For the alanine dipeptide, our methodology identifies ϕ and θ dihedrals as essential degrees of freedom in the C7ax to C7eq transition. For the sarcosine dipeptoid system, the dihedrals ψ and ω are the most important for the cisαD to transαD transition. We further argue that analysis of the full dynamical pathway, and not just endpoint states, is essential for identifying key degrees of freedom governing transitions.

Covalent Organic Framework Based on Azacalix[4]arene for the Efficient Capture of Dialysis Waste Products.

Azacalix[n]arenes (ACAs) are lesser-known cousins of calix[n]arenes that contain amine bridges instead of methylene bridges, so they generally have higher flexibility due to enlarged cavities. Herein, we report a highly substituted cationic azacalix[4]arene-based covalent organic framework (ACA-COF) synthesized by the Zincke reaction under microwave irradiation. The current work is a rare example of a synthetic strategy that utilizes the chemical functionalization of an organic macrocycle to constrain its conformational flexibility and, thereby, produce an ordered material. Considering the ACA cavity dimensions, and the density and diversity of the polar groups in ACA-COF, we used it for adsorption of uric acid and creatinine, two major waste products generated during hemodialysis treatment in patients with renal failure. This type of application, which has the potential to save ∼400 L of water per patient per week, has only been recognized in the last decade, but could effectively address the problem of water scarcity in arid areas of the world. Rapid adsorption rates (up to k = 2191 g mg-1 min-1) were observed in our COF, exceeding reported values by several orders of magnitude.

Refining the RNA Force Field with Small-Angle X-ray Scattering of Helix-Junction-Helix RNA.

The growing recognition of the functional and therapeutic roles played by RNA and the difficulties in gaining atomic-level insights by experiments are paving the way for all-atom simulations of RNA. One of the main impediments to the use of all-atom simulations is the imbalance between the energy terms of the RNA force fields. Through exhaustive sampling of an RNA helix-junction-helix (HJH) model using enhanced sampling, we critically assessed the select Amber force fields against small-angle X-ray scattering (SAXS) experiments. The tested AMBER99SB, DES-AMBER, and CUFIX force fields show deviations from measured profiles. First, we identified parameters leading to inconsistencies. Then, as a way to balance the forces governing RNA folding, we adopted strategies to refine hydrogen bonding, backbone, and base-stacking parameters. We validated the modified force field (HB-CUFIX) against SAXS data of the HJH model in different ionic strengths. Moreover, we tested a set of independent RNA systems to cross-validate the force field. Overall, HB-CUFIX demonstrates improved performance in studying thermodynamics and structural properties of realistic RNA motifs.

Kirkwood-Buff-Derived Force Field for Peptides and Proteins: Philosophy and Development of KBFF20.

A new classical nonpolarizable force field, KBFF20, for the simulation of peptides and proteins is presented. The force field relies heavily on the use of Kirkwood-Buff theory to provide a comparison of simulated and experimental Kirkwood-Buff integrals for solutes containing the functional groups common in proteins, thus ensuring intermolecular interactions that provide a good balance between the peptide-peptide, peptide-solvent, and solvent-solvent distributions observed in solution mixtures. In this way, it differs significantly from other biomolecular force fields. Further development and testing of the intermolecular potentials are presented here. Subsequently, rotational potentials for the ϕ/ψ and χ dihedral degrees of freedom are obtained by analysis of the Protein Data Bank, followed by small modifications to provide a reasonable balance between simulated and observed α and ß percentages for small peptides. This, the first of two articles, describes in detail the philosophy and development behind KBFF20.

Taming the Topology of Calix[4]arene-Based 2D-Covalent Organic Frameworks: Interpenetrated vs Noninterpenetrated Frameworks and Their Selective Removal of Cationic Dyes.

A bowl-shaped calix[4]arene with its exciting host-guest chemistry is a versatile supramolecular building block for the synthesis of distinct coordination cages or metal-organic frameworks. However, its utility in the synthesis of crystalline covalent organic frameworks (COFs) remains challenging, presumably due to its conformational flexibility. Here, we report the synthesis of a periodic 2D extended organic network of calix[4]arenes joined by a linear benzidine linker via dynamic imine bonds. By tuning the interaction among neighboring calixarene units through varying the concentration in the reaction mixture, we show the selective formation of interpenetrated (CX4-BD-1) and non-interpenetrated (CX4-BD-2) frameworks. The cone-shaped calixarene moiety in the structural backbone allows for the interweaving of two neighboring layers in CX4-BD-1, making it a unique example of interpenetrated 2D layers. Due to the high negative surface charge from calixarene units, both COFs have shown high performance in charge-selective dye removal and an exceptional selectivity for cationic dyes irrespective of their molecular size. The charge distribution of the COFs and the resulting selectivity for the cationic dyes were further investigated using computational methods.

A Kirkwood-Buff derived force field for alkaline earth halide salts.

The activity and function of many macromolecules in cellular environments are coupled with the binding of divalent ions such as calcium or magnesium. In principle, computer simulations can be used to understand the molecular level aspects of how many important macromolecules interact with ions. However, most of the force fields currently available often fail to accurately reproduce the properties of divalent ions in aqueous environments. Here we develop classical non-polarizable force fields for the aqueous alkaline earth metal halides (MX2), where M = Mg2+, Ca2+, Sr2+, Ba2+ and X = Cl-, Br-, I-, which can be used in bimolecular simulations and which are compatible with the Simple Point Charge/Extended (SPC/E) water model. The force field parameters are specifically developed to reproduce the experimental Kirkwood-Buff integrals for aqueous solutions and thereby the experimental activity derivatives, partial molar volumes, and excess coordination numbers. This ensures that a reasonable balance between ion-ion, ion-water, and water-water distributions is obtained. However, this requires a scaling of the cation to water oxygen interaction strength in order to accurately reproduce the integrals. The scaling factors developed for chloride salts are successfully transferable to the bromide and iodide salts. Use of these new models leads to reasonable diffusion constants and dielectric decrements. However, the performance of the models decreases with increasing salt concentration (>4m), and simulations of the pure crystals exhibited unstable behavior.