| Description |
Chiral molecules play an important role in many biological processes.1 Important chiral biomolecules include certain amino acids, sugars, DNA, RNA, and many proteins. Chiral molecules have enantiomers, mirror-image isomers that cannot be superimposed on each other. The classic analogy to enantiomers is a pair of hands. A pair of hands mirror each other, yet no matter the orientation of the right hand it remains distinct from the left. This selective "handedness" is also known as chirality. Enantiomers often have very different biological effects, necessitating their separation during the production of pharmaceuticals.2,3 However, most synthetic techniques produce both enantiomers, creating a demand for inexpensive and effective techniques that can separate enantiomers from a racemic solution, a solution that contains a molecule and its enantiomer.3 Spontaneous chiral resolution, the crystallization of a racemic solution into a conglomerate of enantiopure crystals, is a simple, scalable, and inexpensive method of separating enantiomers. However, the majority of organic racemic solutions form racemic crystals rather than enantiopure conglomerates when crystallized.4 It is still unclear why some molecules can spontaneously resolve into separate enantiopure crystals, while the majority form racemic structures.4-6 While simple two-dimensional models have shed some light on the thermodynamics of chiral crystallization7, predictions made with these two-dimensional simulations are not necessarily applicable to three-dimensional systems. In fact, experiments have shown that quasi two-dimensional systems of chiral molecules on the surfaces have a much higher propensity to separate into conglomerates than bulk, three-dimensional, solutions.8 Our recent effort focuses on the development of coarse-grained three-dimensional models of chiral molecules that reproduce the experimentally observed crystallization trends. We develop and analyze a set of three-dimensional molecular dynamics simulations of several coarse-grained models of chiral molecules. Computer simulations represent a promising way to better understand the underlying mechanisms of spontaneous resolution. Simulations can probe the kinetic and thermodynamic factors in the crystallization of chiral molecules9 and can potentially be used to predict the likelihood of spontaneous separation from the properties of a particular chiral molecule. However, straightforward molecular dynamics computer simulations of the crystallization of molecules are plagued by accessible timescales that are much shorter than those of experimental crystallization studies. As a result, crystallization cannot typically be simulated under experimental conditions of mild supersaturation, even if very simple models are used. Under conditions of strong supersaturation, which must be employed in molecular dynamics simulations to enhance solidification rates, many systems fail to crystallize well and form disordered solids instead. To address this challenge, we are developing new computational methods to more closely control the simulation conditions to encourage crystallization. Specifically, we modify the temperature with proportional-integral-derivative (PID) controllers. These controllers monitor a particular quantity during the simulation, such as the maximum cluster size, and modify the temperature on-the-fly to achieve a particular target value. If appropriate parameters are chosen for this controller, we can maintain simulation conditions that facilitate crystal nucleation and growth. By analyzing the crystallization kinetics of several models of three-dimensional chiral crystallization, and by developing an improved method to control the simulation conditions, we aim to predict the likelihood of spontaneous resolution based on molecular structure and interactions. These models and methods provide a valuable basis for further study of chiral crystallization, which may provide useful predictions that suggest whether an organic molecule might spontaneously resolve, allowing pharmaceutical companies to predict the likelihood that a particular chiral drug might separate via spontaneous resolution. |
