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

The dominant driving force of urea-induced protein denaturation is controversial.It is difficult to present the microscopic information such as the dynamic interactions among molecules by experimental methods,and the traditional non-polarizable force field can not reflect the polarization phenomenon.In this thesis,we develop the atom-bond electronegativity equalization fluctuating charge molecular force field（ABEEM/MM）to study the interactions among valine dipeptide-urea-water molecules and further analyze the effect of the charge transfer on the system properties.We construct the ABEEM/MM potential energy function of the valine dipeptide-urea-water system and select[（Val）₂Urea（H₂O）_n]（n=8～10）with total 12 complexes as the training set.The quantum chemistry methods of MP2/aug-cc-p VTZ//B3LYP/6-31G are used to optimize the geometries and compute the binding energies of the training set.Based on QM calculation results,the relevant parameters are optimized.In order to explore the effect of charge transfer among molecules,two different models of charge conservation are established,namely,charge local conservation（LC）model and charge global conservation（GC）model.The difference between them is whether the inter-molecular charge transfer is allowed.Compared with QM,the average absolute deviations（AADs）and root mean square deviations（RMSDs）of bond lengths,bond angles and dihedral angles obtained by LC（GC）model are 0.025?（0.024?）,0.034?（0.033?）;1.51°（1.61°）,2.50°（2.65°）;1.39°（1.63°）,1.99°（2.68°）,respectively.The linear correlation coefficients of charge distributions are all greater than 0.97.The AAD and RMSD of binding energies are 2.29（2.08）kcal·mol^-1 and3.05（2.72）kcal·mol^-1,respectively.Therefore,the two models and the relevant parameters are reasonable.In order to further test the potential energy function and its parameters,they are applied to the larger system[（Val）₂Urea（H₂O）₁₂]with three different conformations.Compared with the QM results,the AADs and RMSDs of bond lengths,bond angles and dihedral angles computed by LC（GC）model are 0.026?（0.027?）,0.036?（0.036?）;1.67°（2.22°）,3.04°（3.64°）;1.25°（1.60°）,1.78°（2.13°）,respectively.The AAD and RMSD of average hydrogen bond lengths are 0.097?（0.124?）and 0.116?（0.149?）,and the AAD and RMSD of average hydrogen bond angles are 2.35°（3.70°）and 3.42°（4.69°）,respectively.The linear correlation coefficients of charge between QM and LC（GC）model are all above 0.98.The AAD and RMSD of binding energies are 2.45（2.86）kcal·mol^-1 and 2.46（3.37）kcal·mol^-1,respectively.It is shown that the geometries,charge distributions and binding energies computed by two models are similar,and the LC model is more consistent with the QM method.It shows that the effect of charge transfer on the above system can be neglected.In summary,ABEEM/MM potential energy function of the valine dipeptide-urea-water system constructed in this thesis can compute the geometries,charge distributions and binding energies,and so on.It lays a foundation for the establishment of the force field for the study of the protein denaturation mechanism of urea.