Development Of ABEEM/MM Fluctuating Charge Molecular Force Field To Study The Interactions Between Urea And Glycine Dipeptide

Urea is a commonly used protein denaturant,but there is still a controversy about the microscopic mechanism of urea-induced protein denaturation.Since most of the force fields employed in molecular simulations are nonpolarizable,the polarization effect cannot be well described.In this thesis,we will develop the atom-bond electronegativity equalization fluctuating charge molecular force field（ABEEM/MM）.Taking the urea-glycine dipeptide-water system as a model system,the ABEEM/MM potential energy function is constructed to explore the interactions between urea,glycine dipeptide and water molecules,as well as the properties of charge polarization and charge transfer.The main contents are as follows:（1）[（Urea）（Gly）₂（H₂O）_n]（n=1～3）are selected as the training set,of which the geometrics and binding energies are studied by the quantum chemistry method MP2/aug-cc-p VTZ//B3LYP/6-31G.Results show that there are three types of hydrogen bonds in the system,C-H…O,O-H…O and N-H…O,among which the bonds strength of O-H…O is slightly stronger than that of the N-H…O,and that of C-H…O is the weakest.The ABEEM/MM fluctuating charge potential energy function of the urea-glycine dipeptide-water system was constructed.The ABEEM/MM parameters are iterativelyd optimized to fit the QM structures,charge distributions and binding energies.（2）The constructed potential energy function are further applied into the larger complex,[（Urea）（Gly）₂（H₂O）_n]（n=12～14）,to test its transferability and reliability.In order to investigate the charge polarization and charge transfer in the system,three ABEEM/MM models with different charge fluctuating and charge conservation constraints are established,namely the non polarizable fixed-charge model（abbreviated as NP）,the fluctuating charge with global conservation constraint model（abbreviated as FQGC）and the fluctuating charge with local conservation constraint model（abbreviated as FQLC）.The difference between the two fluctuating charge models is whether charge transfer between molecules is allowed.Results show that,compared with the QM results,the average absolute deviations（AADs）of bond lengths,bond angles and dihedral angles obtained by the NP model are 0.03（?）,3.18°,and 21.34°,respectively,and the relative root mean square deviation（RRMSD）of the binding energy)is 9.98%.Results from FQLC and FQGC are very close and both are significantly better than those from NP.The AADs of bond lengths,bond angles and dihedral angles obtained from the FQLC and FQGC models are 0.03（?）,2.29°,2.74°and 0.03（?）,2.52°,3.06°,respectively,and the RRMSDs of the binding energy are 1.83%and 1.69%,respectively;the linear correlation coefficients between the charge distributions from both the fluctuating charge models and the QM results are both above 0.98.The above results show that the charge polarization is very important to accurately obtain the structure,energy,etc.of the system;the intermolecular charge transfer effect can be ignored for the system considered here.In summary,the ABEEM/MM potential energy function of the urea-glycine dipeptide-water system constructed here can accurately calculate the structures,charge distributions and binding energies of the urea-glycine dipeptide-water system.This provide an important reference for the further establishment of a fluctuating charge molecular force field that can be applied to explore the microscopic mechanism of urea-induced protein denaturation.