Simulations of biomolecules are becoming ubiquitous, and among other applications, play a central role in protocols for drug discovery. The energy surface determining all thermodynamic, structural, and kinetic properties of these systems is represented in simulations by a force field (FF), and the validity of such simulations depends on the faithfulness by which the FF employed adheres to the actual energy surface of the molecular system. Here we apply a rigorous and powerful assessment of the ability of some of the most widely used FFs to reproduce this energy surface by simulating the thermodynamic and structural properties of a set of amide crystals. Lattice parameters, Hbond geometries packing and intermolecular interactions, inter and intramolecular geometries, and sublimation energies will all be compared to experiment. This will serve both to assess the overall validity of the FFs, and also serve to highlight deficiencies such as H-bond representation, balance of inter and intramolecular forces etc. We note that these high-resolution structural properties are not available from the often-used liquid systems to assess FFs (eg figure1).<br/>This is the initial stage of a project to set up a database of crystal structure and thermodynamic properties to benchmark both current standard FFs for these simulations as well as future FFs to insure that they are indeed justified by improving results over previous FFs. In this initial study we will carry out NPT molecular dynamics studies with the GAFF, CHARMm, OPLS, and current OpenFF (e.g., Thyme) FFs. Here we will report on an initial set of amide compounds including oxamide, malonamide, adipamide, N-Me-acetamide, diketopiperazine, and cyclopropane carboxamide. These display a variety of packing modes, intermolecular interactions and H-bond geometries. They also provide a basic model of the peptide hydrogen-bond as well as alkyl, amide interactions.

Assessing the validity of force field representations through thermodynamic, packing, and structural properties of crystal systems

ACS Spring 2022

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