发展尿素与丙氨酸二肽相互作用的ABEEM/MM可极化力场

Development of ABEEM/MM polarizable force field for the interactions of urea with alanine dipeptide

基于ABEEM/MM浮动电荷模型,尝试建立了一个新的可合理描述尿素-丙氨酸二肽-水分子之间相互作用的可极化力场.采用量子力学(QM)ωB97X-D/6-311++G(3df, 2p)//MP2/aug-cc-pVTZ方法对(Urea)(Ala)2的结构、电荷分布及结合能进行计算,以及HF/STO-3G方法计算电荷分布.构建尿素-丙氨酸二肽-水体系的ABEEM/MM势能函数,基于QM计算结果,优选确定相关参数.结果表明,与QM相比,ABEEM/MM获得的(Urea)(Ala)_(2)的键长、键角、二面角和结合能的AAD(平均绝对偏差),RMSD(均方根偏差)和RRMSD(相对均方根偏差)分别为0.000 8 nm, 0.001 4 nm, 1.2%;1.36°,1.72°,1.5%;4.10°,5.56°,5.0%;6.07 kJ·mol^(-1),6.82 kJ·mol^(-1)和10.2%,电荷分布的线性相关系数为0.988.将上述势能函数应用于(Ala)2(Urea)2(H2O)6体系,以检验势能函数的合理性和参数的可转移性.与QM相比,ABEEM/MM获得的键长、键角、二面角和结合能的AAD,RMSD,RRMSD分别为0.001 0 nm, 0.001 5 nm, 1.3%;1.23°,1.67°,1.5%;1.74°,2.37°,5.5%;9.33 kJ·mol^(-1),10.63 kJ·mol^(-1)和2.7%,电荷分布的线性相关系数为0.984.这表明ABEEM/MM和QM的结果有很好的一致性.所建立的ABEEM/MM势能函数可以合理描述尿素-丙氨酸二肽-水体系的结构、能量和电荷分布,为进一步建立尿素致蛋白质变性微观机制的ABEEM/MM浮动电荷力场打下基础.

The microscopic mechanism of protein denaturation by urea is still unclear,so it is of great significance to reveal it with the aid of molecular simulations.In this work,we attempt to establish a new polarizable force field to reasonably describe the interactions between urea,alanine dipeptide and water molecules based on the ABEEM/MM fluctuating charge model.TheωB97X-D/6-311++G(3df,2p)//MP2/aug-cc-pVTZ level of theory was used to obtain the stable structures and energies of the system concerned,as well as using HF/STO-3G for the charge distributions.The ABEEM/MM potential function for urea-alanine dipeptide-water system was established,and the relevant parameters were optimized based on the QM results of(Urea)(Ala)_(2).Results show that the properties by ABEEM/MM are close to those from QM.Compared with the QM results,the average absolute deviations(AADs),root mean square deviations(RMSDs)and relative root mean square deviations(RRMSDs)of the bond lengths,bond angles,dihedral angles and binding energies from ABEEM/MM are 0.0008 nm,0.0014 nm,1.2%;1.36°,1.72°,1.5%;4.10°,5.56°,5.0%;6.07 kJ·mol^(-1),6.82 kJ·mol^(-1)and 10.2%,respectively.The linear correlation coefficient of charge distributions from ABEEM/MM and QM is 0.988.Then,the ABEEM/MM potential function was applied to study(Ala)_(2)(Urea)_(2)(H_(2)O)_(6) systems to examine the rationality of the potential function and transferability of the parameters.Compared with the QM results,the AADs,RMSDs and RRMSDs of the bond lengths,bond angles,dihedral angles and binding energies from ABEEM/MM are 0.0010 nm,0.0015 nm,1.3%;1.23°,1.67°,1.5%;1.74°,2.37°,5.5%;9.33 kJ·mol^(-1),10.63 kJ·mol^(-1)and 2.7%,respectively.The linear correlation coefficient of charge distributions is 0.984.To sum up,the ABEEM/MM potential function constructed in this work can reasonably describe the structures,energies and charge distributions of the urea-alanine dipeptide-water system,and the results from QM and ABEEM/MM are in good agreements.This work may provide a basis for further establishment of a fluctuating charge force field to explore the microscopic mechanism of the urea-induced protein denaturation.