Crystal Polymorph Search in the NPT Ensemble via a Deposition/Sublimation Alchemical Path

03 November 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The formulation of active pharmaceutical ingredients involves discovering stable crystal packing arrangements, or polymorphs, each of which has distinct pharmaceutically relevant properties. Traditional experimental screening techniques utilizing various conditions are commonly supplemented with in silico crystal structure prediction (CSP) to expedite the crystallization process and mitigate risk. Most predictions are finalized using advanced classical force fields or quantum mechanical calculations that accurately depict the potential energy surface, but do not fully incorporate temperature, pressure or solution conditions during the search. This study proposes an innovative alchemical path that utilizes an advanced polarizable atomic multipole force field to predict crystal structures based on sampling from the NPT ensemble. The use of alchemical (i.e., nonphysical) intermediates, a novel Monte Carlo barostat, and an orthogonal space tempering bias combine to enhance sampling of the deposition/sublimation phase transition and promote an efficient search. The proposed algorithm was applied to 2-((4-(2-(3,4-dichlorophenyl)ethyl)phenyl)amino)benzoic acid (Cambridge Crystallography Database Centre ID: XAFPAY) as a case study to showcase the theory, features and efficiency of this algorithm. All experimentally determined polymorphs with one molecule in the asymmetric unit were successfully reproduced via 1,000 short 1 nsec simulations. Utilizing two threads from a recent Intel® CPU (a Xeon® Gold 6330 CPU at 2.00 GHz) 1 nsec of sampling using the polarizable AMOEBA force field can be acquired in 4 hours (or 336 nsec/day using all 112 threads / 56 cores of the CPU). These results demonstrate a step forward in the rigorous use of the NPT ensemble during a CSP search process and opens the door to future algorithms that incorporate solution conditions using continuum solvation methods.


Crystal Structure Prediction
Alchemical Phase Transition
Force Field
Orthogonal Space Tempering
Force Field X

Supplementary materials

Supplemental Information
SI Figure 1. A diagram describing the steps used to predict the crystal polymorphs. SI Table 1. Predicted polymorphs with RSMD20 to experiment less than 1.5 Å were followed through the pipeline. Impact of Orthogonal Space Tempering (SI Figures 2-4).
Archive of structures (gzip tar file).
A subset of structures produced by the alchemical NPT simulations (using AP20 parameters) have been included as a separate “tar” archive, which also includes the AP20 and AP23 parameters for Compound XXIII.

Supplementary weblinks


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