Abstract
Molecular dynamics (MD) simulation in the explicit water is performed to study the interaction mechanism of trypsin-ligand binding under the AMBER force field and polarized protein-specific charge (PPC) force field combined the new developed highly efficient interaction entropy (IE) method for calculation of entropy change. And the detailed analysis and comparison of the results of MD simulation for two trypsin-ligand systems show that the root-mean-square deviation (RMSD) of backbone atoms, B-factor, intra-protein and protein-ligand hydrogen bonds are more stable under PPC force field than AMBER force field. Our results demonstrate that the IE method is superior than the traditional normal mode (Nmode) method in the calculation of entropy change and the calculated binding free energy under the PPC force field combined with the IE method is more close to the experimental value than other three combinations (AMBER-Nmode, AMBER-IE and PPC-Nmode). And three critical hydrogen bonds between trypsin and ligand are broken under AMBER force field. However, they are well preserved under PPC force field. Detailed binding interactions of ligands with trypsin are further analyzed. The present work demonstrates that the polarized force field combined the highly efficient IE method is critical in MD simulation and free energy calculation.
Highlights
Underlying the interaction mechanism of protein-ligand at atomic level is vital in biomolecular and can provide extremely high value in drug design
The calculated binding free energy of two trypsin systems are analyzed and compared, and our results show that protein-specific charge (PPC) force field with interaction entropy (IE) method is the most optimal combination in Molecular dynamics (MD) simulation and free energy calculation for our systems
In order to appraise the stability of MD simulations equilibrium, the root mean square deviation (RMSD) of the backbone atoms relative to the corresponding native structure as function of time is calculated and shown in the Fig. 1
Summary
Underlying the interaction mechanism of protein-ligand at atomic level is vital in biomolecular and can provide extremely high value in drug design. The current force fields, such as AMBER, CHARMM, GROMOS, OPLS and so on, lack the electronic polarization effect[2,3] which lead inaccurate and unreliable results In these force fields, those charges of residues in proteins are fixed despite of the different surroundings. To provide a more reliable description of the electronic interaction for the binding between protein and ligand, we employ the polarized protein-specific charge (PPC) force[4,5,6] field derived from quantum mechanical calculation for protein and ligand using the molecular fractionation with conjugate caps approach[7]. The above methods are extremely expensive and time-consuming They can only calculate the relative binding free energy[22], so that the application of these two methods in drug design has been greatly limited. The solvation free energy is obtained by the PBSA module in MM/PBSA method and the entropy contribution is calculated by IE method during the calculation of the binding free energy
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