Multi-scale Simulation Study On The Selectivity Of Parvalbumin B Protein To Magnesium And Calcium Ions

Protein is an indispensable and important component of living organisms.They associate with various metal ions to play diverse functions in life processes.Therefore,exploring the selectivity of proteins to metal ions is of great significance for the study of individual organisms and drug design.Ion selectivity can be characterized by the free energy difference in the protein/ion binding process.Free energy calculations are nowadays quite mature and are widely used in materials design,drug design,and many other biochemical fields.An ideal free energy calculation should save the calculation cost as much as possible under the premise of ensuring accuracy.Quantum mechanics(QM)methods based on density functional theory(DFT)provide a suitable model for describing the interaction between particles,which maintain a balance between accuracy and efficiency.However,free energy calculations usually require a long sampling in phase space,and it can be formidably expensive at this level of theory.On the other end of this spectrum of methods is the molecular mechanics(MM)methods,which can be quite efficiency in generating samples,sacrificing some accuracy more or less.In this thesis,the calculation of the relative binding free energy of a calcium ion and a magnesium ion with Parvalbumin B protein under a QM Hamiltonian via RPM is presented.The relative binding free energy difference(?)G is decomposed into the free energy difference between the two ions in aqueous solution(?)G_Lig and the free energy difference in protein complex(?)G_Com.The relative binding free energy difference between the two ions with the Parvalbumin B protein under the reference potential energy surface(?)G^MM was calculated by running alchemical transformations of the ions in the aqueous solution and in the protein complex respectively.Then,the free energy differences between the reference potential energy surface and the target potential energy surface of the end-to-end states were calculated,thereby correcting the free energy result calculated under the low-level Hamiltonian to the high-level potential energy surface.In this way,the relative binding free energy difference under the QM Hamiltonian was obtained.The result shows that the RPM is reliable and converges very quickly,and it also shows that the electronic response,which is sometimes called the quantum effect in a naive way,beyond the point charge model is dispensable for the selectivity calculations of metal ions binding with proteins.