Crystal Polymorph Search in the NPT Ensemble via a Deposition/Sublimation Alchemical Path
Crystal Polymorph Search in the NPT Ensemble via a Deposition/Sublimation Alchemical Path
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DOI：
10.1021/acs.cgd.3c01358
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发表时间：
2024-03-09
影响因子：
3.8
通讯作者：
Schnieders，Michael J.
中科院分区：
文献类型：
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作者：
Nessler，Aaron J.;Okada，Okimasa;Schnieders，Michael J.
活性药物成分的配制涉及发现稳定的晶体堆积排列或多晶型物，其各自具有不同的药学相关性质。利用各种条件的传统实验筛选技术通常辅以计算机晶体结构预测（CSP），以告知结晶过程并降低风险。预测通常基于先进的经典力场或量子力学计算，这些计算对晶体势能景观进行建模，但在搜索过程中没有完全考虑温度，压力或溶液条件。这项研究提出了一个创新的炼金术路径，利用先进的极化原子多极力场预测晶体结构的基础上直接采样的NPTeneplane。炼金术的使用（即，非物理的）中间体、新颖的蒙特卡罗恒压器和正交空间回火偏置联合收割机组合以增强沉积/升华相变的采样效率。将所提出的算法应用于2-（（4-（2-（3，4-二氯苯基）乙基）苯基）氨基）苯甲酸（剑桥晶体学数据库中心ID：XAFPAY）作为案例研究来展示该算法。通过每个空间群大约1000个短的1 ns模拟成功地再现了在不对称单元中具有一个分子的每个实验确定的多晶型物，其中每个模拟从随机刚体坐标和晶胞参数开始。利用最新的Intel CPU（Xeon Gold 6330 CPU，2.00 GHz）的两个线程，在Force Field X软件（https：//www.example.com）中，使用可极化AMOEBA力场可以在4小时内获得1 ns的采样（相当于使用双CPU节点的所有112个线程/56个内核超过300 ns/天）。ffx.biochem.uiowa.edu这些结果表明，在CSP搜索过程中，严格使用theNPTengland向前迈出了一步，并打开了大门，未来的算法，将解决方案的条件，使用连续溶剂化方法。
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 theNPTensemble. 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 theNPTensemble during the CSP search process and open the door to future algorithms that incorporate solution conditions using continuum solvation methods.