The presence of multiple stable crystal structures in solid organic materials can limit their commercial viability when two or more observable polymorphs exhibit markedly different physical properties. Crystallography researchers estimate that 50% of all drug molecules exhibit polymorphism, but only 1% of the materials with a well-characterized crystal structure in national crystal structure databases contain a similar level of data for an alternative polymorph structure.
Current computational methods for predicting polymorphic behavior generate many possible crystal structures and rapidly evaluate the lattice energies of these candidate structures to determine the most likely to be observed experimentally. However, lattice energies alone do not fully capture the stability of systems that are at room temperature and sample a range of configurations due to thermal motion. In addition, ab initio quantum mechanical models or at minimum polarizable force fields are likely necessary to represent the physical system, but the extensive sampling required in molecular dynamics can currently only be performed with classical point-charge force fields.
In this work, we present an atomistic simulation approach to evaluate the free energy difference between crystal polymorphs in both computationally cheap and expensive Hamiltonians. Molecular dynamics simulations are conducted in a classical point-charge all-atom potential designed to overlap with the expensive Hamiltonian. Multistate Hamiltonian reweighting is then employed on these configurations post simulation to estimate the free energy difference in more expensive force fields without any additional sampling. We therefore access computationally demanding free energy differences by avoiding direct simulation within the polarizable potentials.
This simulation technique is applied to solid phase benzene, which is known to have multiple distinct polymorphs. We reweight to polarizable potentials and the simulation results indicate that the exact polymorph stability is strongly sensitive to the choice of Hamiltonian. Furthermore, the successful Hamiltonian reweighting technique demonstrates that the relevant phase space of polarizable Hamiltonians in this system can be approximated using only point-charge models. These preliminary results represent a significant step toward the ultimate goal of tractable thermodynamic calculations using more expensive many-body energies.
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