Journal article
Crystal Polymorph Search in the NPT Ensemble via a Deposition/Sublimation Alchemical Path
Crystal growth & design, Vol.24(8), pp.3205-3217
04/17/2024
DOI: 10.1021/acs.cgd.3c01358
PMCID: PMC11036363
PMID: 38659664
Appears in UI Libraries Support Open Access
Abstract
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 inform the crystallization process and mitigate risk. Predictions are often based on advanced classical force fields or quantum mechanical calculations that model the crystal potential energy landscape but do not fully incorporate temperature, pressure, or solution conditions during the search procedure. This study proposes an innovative alchemical path that utilizes an advanced polarizable atomic multipole force field to predict crystal structures based on direct sampling of 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 the sampling efficiency of the deposition/sublimation phase transition. 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 algorithm. Each experimentally determined polymorph with one molecule in the asymmetric unit was successfully reproduced via approximately 1000 short 1 ns simulations per space group where each simulation was initiated from random rigid body coordinates and unit cell parameters. Utilizing two threads of a recent Intel CPU (a Xeon Gold 6330 CPU at 2.00 GHz), 1 ns of sampling using the polarizable AMOEBA force field can be acquired in 4 h (equating to more than 300 ns/day using all 112 threads/56 cores of a dual CPU node) within the Force Field X software (https://ffx.biochem.uiowa.edu). These results demonstrate a step forward in the rigorous use of the NPT ensemble during the CSP search process and open the door to future algorithms that incorporate solution conditions using continuum solvation methods.
Details
- Title: Subtitle
- Crystal Polymorph Search in the NPT Ensemble via a Deposition/Sublimation Alchemical Path
- Creators
- Aaron J. Nessler - Univ Iowa, Dept Biomed Engn, Iowa City, IA 52242 USAOkimasa Okada - University of Iowa, Iowa Technology InstituteYuya Kinoshita - TakedaKoki Nishimura - TakedaHiroomi Nagata - Mitsubishi Tanabe Pharma Corp, Prod Technol & Supply Chain Management Div, CMC Modal Technol Labs, Osaka 5418505, JapanKaori Fukuzawa - Osaka UniversityEtsuo Yonemochi - Hoshi UniversityMichael J. Schnieders - University of Iowa, Roy J. Carver Department of Biomedical Engineering
- Resource Type
- Journal article
- Publication Details
- Crystal growth & design, Vol.24(8), pp.3205-3217
- Publisher
- American Chemical Society
- DOI
- 10.1021/acs.cgd.3c01358
- PMID
- 38659664
- PMCID
- PMC11036363
- ISSN
- 1528-7483
- eISSN
- 1528-7505
- Number of pages
- 13
- Grant note
- hp220243 / National Institute on Deafness and Other Communication Disorders; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Deafness & Other Communication Disorders (NIDCD) Riken Center through the HPCI System Research Project
- Language
- English
- Electronic publication date
- 03/09/2024
- Date published
- 04/17/2024
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Biochemistry and Molecular Biology; Chemical and Biochemical Engineering
- Record Identifier
- 9984585957102771
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