Accurately estimating protein–ligand binding free energy is crucial for drug design and biophysics, yet remains a challenging task. In this study, we applied the screening molecular mechanics/Poisson–Boltzmann surfa...Accurately estimating protein–ligand binding free energy is crucial for drug design and biophysics, yet remains a challenging task. In this study, we applied the screening molecular mechanics/Poisson–Boltzmann surface area(MM/PBSA)method in combination with various machine learning techniques to compute the binding free energies of protein–ligand interactions. Our results demonstrate that machine learning outperforms direct screening MM/PBSA calculations in predicting protein–ligand binding free energies. Notably, the random forest(RF) method exhibited the best predictive performance,with a Pearson correlation coefficient(rp) of 0.702 and a mean absolute error(MAE) of 1.379 kcal/mol. Furthermore, we analyzed feature importance rankings in the gradient boosting(GB), adaptive boosting(Ada Boost), and RF methods, and found that feature selection significantly impacted predictive performance. In particular, molecular weight(MW) and van der Waals(VDW) energies played a decisive role in the prediction. Overall, this study highlights the potential of combining machine learning methods with screening MM/PBSA for accurately predicting binding free energies in biosystems.展开更多
葡萄糖激酶(glucokinase,GK)催化葡萄糖转变为6-磷酸葡萄糖,是糖代谢的第一步,所以GK活性异常在糖代谢紊乱的发生发展中起着重要作用.对青年型早发糖尿病(maturity-onset diabetes of the young 2,MODY 2)型和高胰岛素性低血糖症(persis...葡萄糖激酶(glucokinase,GK)催化葡萄糖转变为6-磷酸葡萄糖,是糖代谢的第一步,所以GK活性异常在糖代谢紊乱的发生发展中起着重要作用.对青年型早发糖尿病(maturity-onset diabetes of the young 2,MODY 2)型和高胰岛素性低血糖症(persistent hyperinsulinemic hypoglycemia of infancy,PHHI)型的深入研究证实了GK活性改变与糖尿病的发生有关.为了研究GK活性改变的机理,通过分子动力学模拟和隐性溶剂的自由能的计算对GK的单点突变M197V(Met197→Val)进行了理论研究.通过GK的Cα原子均方根浮动变化(Root mean square fluctuation,RMSF)和动态相关性矩阵(Dynamic cross-correlation matrices,DCCM)分析,显示M197V突变导致GK在活化状态的构象更加稳定.通过包结自由能分析,表明M197V突变可以增加GK对葡萄糖的包结亲合性,并且理论预测突变前后的相对包结自由能差值和已有的实验结果非常吻合.研究结果很好地从原子水平解释了GK的M197V突变的活化机理.展开更多
Poly(glycolic acid)(PGA)is derived from glycolide obtained by fermenting pineapples or sugarcane,which has excellent gas barrier properties and a small carbon footprint.PGA is a potential substitute for the current al...Poly(glycolic acid)(PGA)is derived from glycolide obtained by fermenting pineapples or sugarcane,which has excellent gas barrier properties and a small carbon footprint.PGA is a potential substitute for the current aluminum-plastic composite films used in high barrier packaging applications.However,its poor ductility and narrow processing window limit its application in food packaging.Herein,poly(butylene succinate-co-butylene adipate)(PBSA)was used to fabricate PGA/PBSA blend films through an in situ fibrillation technique and blown film extrusion.Under the elongational flow field used during the extrusion process,a unique hierarchical structure based on the PBSA nanofibrils and interfacially oriented PGA crystals was obtained.This structure enhances the strength,ductility and gas barrier properties of the PGA/PBSA blend film.In addition,an epoxy chain extender(ADR4468)was used as a compatibilizer to further enhance the interfacial adhesion between PGA and PBSA.70PGA/0.7ADR exhibited a very low oxygen permeability(2.34×10^(-4)Barrer)with significantly high elongating at break(604.4%),tensile strength(47.4 MPa),and transparency,which were superior to those of petroleum-based polymers.Thus,the 70PGA/0.7ADR blown films could satisfy the requirements for most instant foods such as coffee,peanuts,and fresh meat.展开更多
基金Project supported by the National Natural Science Foundation of China (Grant Nos. 12222506, 12347102, 12447164, and 12174184)。
文摘Accurately estimating protein–ligand binding free energy is crucial for drug design and biophysics, yet remains a challenging task. In this study, we applied the screening molecular mechanics/Poisson–Boltzmann surface area(MM/PBSA)method in combination with various machine learning techniques to compute the binding free energies of protein–ligand interactions. Our results demonstrate that machine learning outperforms direct screening MM/PBSA calculations in predicting protein–ligand binding free energies. Notably, the random forest(RF) method exhibited the best predictive performance,with a Pearson correlation coefficient(rp) of 0.702 and a mean absolute error(MAE) of 1.379 kcal/mol. Furthermore, we analyzed feature importance rankings in the gradient boosting(GB), adaptive boosting(Ada Boost), and RF methods, and found that feature selection significantly impacted predictive performance. In particular, molecular weight(MW) and van der Waals(VDW) energies played a decisive role in the prediction. Overall, this study highlights the potential of combining machine learning methods with screening MM/PBSA for accurately predicting binding free energies in biosystems.
文摘葡萄糖激酶(glucokinase,GK)催化葡萄糖转变为6-磷酸葡萄糖,是糖代谢的第一步,所以GK活性异常在糖代谢紊乱的发生发展中起着重要作用.对青年型早发糖尿病(maturity-onset diabetes of the young 2,MODY 2)型和高胰岛素性低血糖症(persistent hyperinsulinemic hypoglycemia of infancy,PHHI)型的深入研究证实了GK活性改变与糖尿病的发生有关.为了研究GK活性改变的机理,通过分子动力学模拟和隐性溶剂的自由能的计算对GK的单点突变M197V(Met197→Val)进行了理论研究.通过GK的Cα原子均方根浮动变化(Root mean square fluctuation,RMSF)和动态相关性矩阵(Dynamic cross-correlation matrices,DCCM)分析,显示M197V突变导致GK在活化状态的构象更加稳定.通过包结自由能分析,表明M197V突变可以增加GK对葡萄糖的包结亲合性,并且理论预测突变前后的相对包结自由能差值和已有的实验结果非常吻合.研究结果很好地从原子水平解释了GK的M197V突变的活化机理.
基金the National Key Research and Development Program of China(No.2022YFB3704900)the National Natural Science Foundation of China(No.52073004)China National Tobacco Corporation Guizhou Company(No.2023XM24)。
文摘Poly(glycolic acid)(PGA)is derived from glycolide obtained by fermenting pineapples or sugarcane,which has excellent gas barrier properties and a small carbon footprint.PGA is a potential substitute for the current aluminum-plastic composite films used in high barrier packaging applications.However,its poor ductility and narrow processing window limit its application in food packaging.Herein,poly(butylene succinate-co-butylene adipate)(PBSA)was used to fabricate PGA/PBSA blend films through an in situ fibrillation technique and blown film extrusion.Under the elongational flow field used during the extrusion process,a unique hierarchical structure based on the PBSA nanofibrils and interfacially oriented PGA crystals was obtained.This structure enhances the strength,ductility and gas barrier properties of the PGA/PBSA blend film.In addition,an epoxy chain extender(ADR4468)was used as a compatibilizer to further enhance the interfacial adhesion between PGA and PBSA.70PGA/0.7ADR exhibited a very low oxygen permeability(2.34×10^(-4)Barrer)with significantly high elongating at break(604.4%),tensile strength(47.4 MPa),and transparency,which were superior to those of petroleum-based polymers.Thus,the 70PGA/0.7ADR blown films could satisfy the requirements for most instant foods such as coffee,peanuts,and fresh meat.
