Communications: Electron polarization critically stabilizes the Mg2+ complex in the catalytic core domain of HIV-1 integrase

Abstract

In this paper, we present a detailed dynamics study of the catalytic core domain (CCD) of HIV-1 integrase using both polarized and nonpolarized force fields. The numerical results reveal the critical role of protein polarization in stabilizing Mg2+ coordination complex in CCD. Specifically, when nonpolarized force field is used, a remarkable drift of the Mg2+ complex away from its equilibrium position is observed, which causes the binding site blocked by the Mg2+ complex. In contrast, when polarized force field is employed in MD simulation, HIV-1 integrase CCD structure is stabilized and both the position of the Mg2+ complex and the binding site are well preserved. The detailed analysis shows the transition of α-helix to 310-helix adjacent to the catalytic loop (residues 139–147), which correlates with the dislocation of the Mg2+ complex. The current study demonstrates the importance of electronic polarization of protein in stabilizing the metal complex in the catalytic core domain of HIV-1 integrase.

Theoretical study on the HIV-1 integrase–5CITEP complex based on polarized force fields

“…In crystal form, crystal packing effect may change the shape of the binding site. The important effect of electrostatic polarization on protein dynamics has also been observed in previous studies [33,34]. Since PPC for IN-5CITEP is derived from quantum mechanical calculation of the entire protein complex in solution, it includes the change of polarization for residues both inside the IN and at the site directly involved in 5CITEP binding into the atomic charges and thus correctly represents electronically polarized state of the complex structure.…”

“…Since the PPC is derived by charge fitting to electrostatic potential (RESP) [25,26] from the quantum mechanical calculation of the protein in continuous solvent using the molecular fraction with conjugate caps (MFCC) approach [27][28][29][30][31][32] and Poisson-Boltzmann solvation model, it contains the proper polarization effect and should provide more reliable description of the highly polar environment around the ligand 5CI-TEP. Previous studies [33,34] showing the important role of PPC in stabilizing the protein dynamic behavior make us believe that PPC can benefit long-time scale simulation of protein-ligand complex system especially for HIV-1 IN-5CITEP complex. Specifically, the MD simulations in this Letter are performed under two charge models, i.e.…”

Folding and thermodynamic studies of Trp-cage based on polarized force field

“…It contains the proper polarization effect, which should hence provide more reliable description in protein dynamics. Recent works also support the stand that using PPC can give a good description of the native structure [39,40]. Thus, in this work, we employ PPC to include polarization effect to study the thermodynamic properties, that is, the population of folded state in various temperatures.…”

FEREBUS: Highly parallelized engine for kriging training

“…However, ab initio calculations are suitable only for small systems or short time scales, and larger systems or longer time scales can only be approximated through the use of a force field. Unfortunately, most force fields are not able to correctly reproduce a number of critical properties, in particular for biological molecules (hydrogen bonding, structure, π stacking, amino acid pK a shifts) …”