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  1. Abstract

    Short hydrogen bonds (SHBs), whose donor and acceptor heteroatoms lie within 2.7 Å, exhibit prominent quantum mechanical characters and are connected to a wide range of essential biomolecular processes. However, exact determination of the geometry and functional roles of SHBs requires a protein to be at atomic resolution. In this work, we analyze 1260 high-resolution peptide and protein structures from the Protein Data Bank and develop a boosting based machine learning model to predict the formation of SHBs between amino acids. This model, which we name as machine learning assisted prediction of short hydrogen bonds (MAPSHB), takes into account 21 structural, chemical and sequence features and their interaction effects and effectively categorizes each hydrogen bond in a protein to a short or normal hydrogen bond. The MAPSHB model reveals that the type of the donor amino acid plays a major role in determining the class of a hydrogen bond and that the side chain Tyr-Asp pair demonstrates a significant probability of forming a SHB. Combining electronic structure calculations and energy decomposition analysis, we elucidate how the interplay of competing intermolecular interactions stabilizes the Tyr-Asp SHBs more than other commonly observed combinations of amino acid side chains. The MAPSHB model,more »which is freely available on our web server, allows one to accurately and efficiently predict the presence of SHBs given a protein structure with moderate or low resolution and will facilitate the experimental and computational refinement of protein structures.

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  2. Acid–base chemistry has immense importance for explaining and predicting the chemical products formed by an acid and a base when mixed together. However, the traditional chemistry theories used to describe acid–base reactions do not take into account the effect arising from the quantum mechanical nature of the acidic hydrogen shuttling potential and its dependence on the acid base distance. Here, infrared and NMR spectroscopies, in combination with first principles simulations, are performed to demonstrate that quantum mechanical effects, including electronic and nuclear quantum effects, play an essential role in defining the acid–base chemistry when 1-methylimidazole and acetic acid are mixed together. In particular, it is observed that the acid and the base interact to form a complex containing a strong hydrogen bond, in which the acidic hydrogen atom is neither close to the acid nor to the base, but delocalized between them. In addition, the delocalization of the acidic hydrogen atom in the complex leads to characteristic IR and NMR signatures. The presence of a hydrogen delocalized state in this simple system challenges the conventional knowledge of acid–base chemistry and opens up new avenues for designing materials in which specific properties produced by the hydrogen delocalized state can be harvested.
    Free, publicly-accessible full text available June 15, 2023
  3. Short hydrogen bonds (SHBs), which have donor and acceptor separations below 2.7 Å, occur extensively in small molecules and proteins. Due to their compact structures, SHBs exhibit prominent covalent characters with elongated Donor–H bonds and highly downfield (>14 ppm) 1 H NMR chemical shifts. In this work, we carry out first principles simulations on a set of model molecules to assess how quantum effects determine the symmetry and chemical shift of their SHBs. From simulations that incorporate the quantum mechanical nature of both the electrons and nuclei, we reveal a universal relation between the chemical shift and the position of the proton in a SHB, and unravel the origin of the observed downfield spectral signatures. We further develop a metric that allows one to accurately and efficiently determine the proton position directly from its 1 H chemical shift, which will facilitate the experimental examination of SHBs in both small molecules and biological macromolecules.
  4. At room temperature, the quantum contribution to the kinetic energy of a water molecule exceeds the classical contribution by an order of magnitude. The quantum kinetic energy (QKE) of a water molecule is modulated by its local chemical environment and leads to uneven partitioning of isotopes between different phases in thermal equilibrium, which would not occur if the nuclei behaved classically. In this work, we use ab initio path integral simulations to show that QKEs of the water molecules and the equilibrium isotope fractionation ratios of the oxygen and hydrogen isotopes are sensitive probes of the hydrogen bonding structures in aqueous ionic solutions. In particular, we demonstrate how the QKE of water molecules in path integral simulations can be decomposed into translational, rotational and vibrational degrees of freedom, and use them to determine the impact of solvation on different molecular motions. By analyzing the QKEs and isotope fractionation ratios, we show how the addition of the Na + , Cl − and HPO 4 2− ions perturbs the competition between quantum effects in liquid water and impacts their local solvation structures.
  5. Correction for ‘Unraveling the structural and chemical features of biological short hydrogen bonds’ by Shengmin Zhou et al., Chem. Sci. , 2019, DOI: 10.1039/c9sc01496a.
  6. The three-dimensional architecture of biomolecules often creates specialized structural elements, notably short hydrogen bonds that have donor–acceptor separations below 2.7 Å. In this work, we statistically analyze 1663 high-resolution biomolecular structures from the Protein Data Bank and demonstrate that short hydrogen bonds are prevalent in proteins, protein–ligand complexes and nucleic acids. From these biological macromolecules, we characterize the preferred location, connectivity and amino acid composition in short hydrogen bonds and hydrogen bond networks, and assess their possible functional importance. Using electronic structure calculations, we further uncover how the interplay of the structural and chemical features determines the proton potential energy surfaces and proton sharing conditions in biological short hydrogen bonds.