100th Anniversary of Macromolecular Science Viewpoint: Modeling and Simulation of Macromolecules with Hydrogen Bonds: Challenges, Successes, and Opportunities

Abstract

Macromolecular materials with directional interactions such as hydrogen bonds exhibit numerous attractive features in terms of structure, thermodynamics, and dynamics. Besides enabling precise tuning of desirable geometries in the assembled state (e.g., programmable coordination numbers depending on the valency of the directional interaction), mixing in a blend/composite through stabilization via hydrogen bonds between the various components, hydrogen bonds can also impart responsiveness to external stimuli (e.g., temperature, pH). In biomacromolecules (e.g., proteins, DNA, polysaccharides), hydrogen bonds play a key role in stabilizing secondary and tertiary structures, which in turn define the function of these macromolecules. In this Viewpoint, I present the challenges, successes, and opportunities for molecular modeling and simulations to conduct fundamental and application-focused research on macromolecular materials with hydrogen bonding interactions. The past successes and limitations of atomistic simulations are discussed first, followed by highlights from recent developments in coarse-grained modeling and their use in studies of (synthetic and biologically relevant) macromolecular materials. Model development focused on polynucleotides (e.g., DNA, RNA, etc.), polypeptides, polysaccharides, and synthetic polymers at experimentally relevant conditions are highlighted. This viewpoint ends with potential future directions for macromolecular modeling and simulations with other types of directional interactions beyond hydrogen bonding.

Hydrogen Bonding in Natural and Unnatural Base Pairs—A Local Vibrational Mode Study

“…A key feature of the base pairs is their link via hydrogen bonds (HB) [ 40 , 41 , 42 , 43 , 44 , 45 ]. Therefore, a comprehensive study of the hydrogen bonds formed between the base pairs is imperative (i) for the deeper understanding of the structure and biological function of DNA, and (ii) to assess the qualification of designer UBP .…”

“…Already in the 1950s Linus Pauling explored together with Robert B. Corey the importance of hydrogen bonding in proteins [ 46 , 47 , 48 ], work which contributed to his Nobel Price in Chemistry, awarded to him in 1954 for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances [ 49 , 50 ]. Up to now HBs have been the object of numerous experimental and theoretical investigations [ 45 , 51 , 52 , 53 ], and because of the complex interplay between different components, their nature is still subject of an ongoing debate [ 41 , 42 , 54 ]. Using intermolecular HBs as the key feature of base pairs selectivity GC base pairs with different bonding patterns and atomic organization were suggested [ 55 , 56 ], as well as different UBP estimating the HBs via calculated interaction energies [ 57 ].…”

Chemically specific coarse‐graining of polymers: Methods and prospects

“…167,168 The latter strategy (creating effectively "patchy" CG beads) yields reduced model complexity and computational cost, since the all sites remain isotropic. 169 This patchy particle approach (Figure 2D) has been used by Jayaraman et al to model collagen-like peptides, 170 α-1,3-glucan, 171 and cellulose. 155 Anisotropic potentials can also be used with coarser representations to capture phenomena at larger lengthscales.…”

Development of Coarse-Grained Models for Poly(4-vinylphenol) and Poly(2-vinylpyridine): Polymer Chemistries with Hydrogen Bonding

“…One subset of top-down CG models is phenomenological CG models, which are intuitively parameterized to correctly represent an observed phenomenon. The CG model development highlighted in this paper falls within this subset of phenomenological CG models and is focused on macromolecules that exhibit directional interactions [ 87 ].…”

“…In past studies, CG models utilized simple isotropic potentials, which inherently lack directionality, to describe hydrogen bonding interactions in polymers [ 87 , 103 ]. However, it has been realized that to reproduce the effect of hydrogen bonds, the incorporation of effective directionality or anisotropic interactions in the CG model is essential, as hydrogen bonding in polymers brings about a valency effect structurally and also imposes rotational constraints on interacting atoms, leading to significant changes in entropy as compared to isotropic interactions [ 91 , 92 , 104 ].…”