Simulation of NMR Data Reveals That Proteins’ Local Structures Are Stabilized by Electronic Polarization

Abstract

Molecular dynamics simulations of NMR backbone relaxation order parameters have been carried out to investigate the polarization effect on the protein's local structure and dynamics for five benchmark proteins (bovine pancreatic trypsin inhibitor, immunoglobulin-binding domain (B1) of streptococcal protein G, bovine apo-calbindin D9K, human interleukin-4 R88Q mutant, and hen egg white lysozyme). In order to isolate the polarization effect from other interaction effects, our study employed both the standard AMBER force field (AMBER03) and polarized protein-specific charges (PPCs) in the MD simulations. The simulated order parameters, employing both the standard nonpolarizable and polarized force fields, are directly compared with experimental data. Our results show that residue-specific order parameters at some specific loop and turn regions are significantly underestimated by the MD simulations using the standard AMBER force field, indicating hyperflexibility of these local structures. Detailed analysis of the structures and dynamic motions of individual residues reveals that the hyperflexibility of these local structures is largely related to the breaking or weakening of relevant hydrogen bonds. In contrast, the agreement with the experimental results is significantly improved and more stable local structures are observed in the MD simulations using the polarized force field. The comparison between theory and experiment provides convincing evidence that intraprotein hydrogen bonds in these regions are stabilized by electronic polarization, which is critical to the dynamical stability of these local structures in proteins.

Assessing and refining molecular dynamics simulations of proteins with nuclear magnetic resonance data

“…3), but sometimes struggled to reproduce NMR data averaged over longer time-scales (Brüschweiler et al 1992;Chandrasekhar et al 1992;Koerdel and Teleman 1992;Palmer and Case 1992;Eriksson et al 1993;Smith et al 1995a, b;Nanzer et al 1997). Even in more recent studies, the agreement with experimental data is often worst for residues in loops or disordered regions (Wrabl et al 2000;Tong et al 2009); in some cases, these regions are simply excluded from the analysis .…”

Communication: The electrostatic polarization is essential to differentiate the helical propensity in polyalanine mutants

“…The quantum mechanical calculation is carried out using a molecular tailoring method termed the molecular fractionation with conjugate caps (MFCC) and PoissonBoltzmann solvation model. 21,22 This charge model has been successfully applied to several studies such as secondary structure stability, 23,24 pKa of titratable side chains, 19 and protein-ligand binding. 25 In this paper, we employ adaptive hydrogen bondspecific charge (AHBC) in molecular dynamics simulation to perform the folding process of a series of polyalanine peptides introduced by Baldwin et al 26 The guest amino acids are substituted at one or more positions of the alaninebased peptides which cause the distinction of conformations of peptides in various solutions, according to the results obtained from several predominant techniques such as circular dichroism (CD) measurements.…”

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

“…Its advantage over conventional nonpolarizable FF has been demonstrated by a number of benchmark applications. [29][30][31] In this work, we employed PPC together with quantum treatment for the metal coordination complex to include polarization effect to study the time evolution of catalytic core domain in HIV-1 IN, focusing on the variations of both the secondary structure and the shape of the binding pocket. These results are explicitly compared with those from conventional FF calculations ͑AMBER03͒ to gain insight on the effect of protein polarization in the dynamics of metal ion coordination complex.…”