Streamlining Linear Free Energy Relationships of Proteins through Dimensionality Analysis and Linear Modeling.

IF 5.6 2区 化学 Q1 CHEMISTRY, MEDICINAL
Muhammad Irfan Khawar, Muhammad Arshad, Eric P Achterberg, Deedar Nabi
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引用次数: 0

Abstract

Linear free energy relationships (LFERs) are pivotal in predicting protein-water partition coefficients, with traditional one-parameter (1p-LFER) models often based on octanol. However, their limited scope has prompted a shift toward the more comprehensive but parameter-intensive Abraham solvation-based poly-parameter (pp-LFER) approach. This study introduces a two-parameter (2p-LFER) model, aiming to balance simplicity and predictive accuracy. We showed that the complex six-dimensional intermolecular interaction space, defined by the six Abraham solute descriptors, can be efficiently simplified into two key dimensions. These dimensions are effectively represented by the octanol-water (log Kow) and air-water (log Kaw) partition coefficients. Our 2p-LFER model, utilizing linear combinations of log Kow and log Kaw, showed promising results. It accurately predicted structural protein-water (log Kpw) and bovine serum albumin-water (log KBSA) partition coefficients, with R2 values of 0.878 and 0.760 and root mean squared errors (RMSEs) of 0.334 and 0.422, respectively. Additionally, the 2p-LFER model favorably compares with pp-LFER predictions for neutral per- and polyfluoroalkyl substances. In a multiphase partitioning model parametrized with 2p-LFER-derived coefficients, we observed close alignment with experimental in vivo and in vitro distribution data for diverse mammalian tissues/organs (n = 137, RMSE = 0.44 log unit) and milk-water partitioning data (n = 108, RMSE = 0.29 log units). The performance of the 2p-LFER is comparable to pp-LFER and significantly surpasses 1p-LFER. Our findings highlight the utility of the 2p-LFER model in estimating chemical partitioning to proteins based on hydrophobicity, volatility, and solubility, offering a viable alternative in scenarios where pp-LFER descriptors are unavailable.

通过量纲分析和线性建模简化蛋白质的线性自由能关系。
线性自由能关系(lfer)是预测蛋白质-水分配系数的关键,传统的单参数(1p-LFER)模型通常基于辛醇。然而,他们有限的范围促使转向更全面但参数密集的亚伯拉罕溶剂化多参数(pp-LFER)方法。本研究引入了一种双参数(2p-LFER)模型,旨在平衡简单性和预测准确性。我们证明了由六个亚伯拉罕溶质描述符定义的复杂的六维分子间相互作用空间可以有效地简化为两个关键维度。这些维度由辛醇-水(对数对数)和空气-水(对数对数)分配系数有效地表示。我们的2p-LFER模型,利用log Kow和log Kow的线性组合,显示出令人鼓舞的结果。准确预测结构蛋白-水(log Kpw)和牛血清白蛋白-水(log KBSA)分配系数,R2值分别为0.878和0.760,均方根误差(rmse)分别为0.334和0.422。此外,2p-LFER模型与pp-LFER模型对中性全氟烷基和多氟烷基物质的预测结果进行了比较。在以2p- lfe衍生系数参数化的多相分配模型中,我们观察到与实验中不同哺乳动物组织/器官的体内和体外分布数据(n = 137, RMSE = 0.44 log units)和牛奶-水分配数据(n = 108, RMSE = 0.29 log units)非常吻合。2p-LFER的性能与pp-LFER相当,并显著优于1p-LFER。我们的研究结果强调了2p-LFER模型在基于疏水性、挥发性和溶解度估计蛋白质化学分配方面的实用性,在pp-LFER描述符不可用的情况下提供了一个可行的替代方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.80
自引率
10.70%
发文量
529
审稿时长
1.4 months
期刊介绍: The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery. Astute chemists, computer scientists, and information specialists look to this monthly’s insightful research studies, programming innovations, and software reviews to keep current with advances in this integral, multidisciplinary field. As a subscriber you’ll stay abreast of database search systems, use of graph theory in chemical problems, substructure search systems, pattern recognition and clustering, analysis of chemical and physical data, molecular modeling, graphics and natural language interfaces, bibliometric and citation analysis, and synthesis design and reactions databases.
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