Folding of a Helix at Room Temperature Is Critically Aided by Electrostatic Polarization of Intraprotein Hydrogen Bonds

Abstract

We report direct folding of a 17-residue helix protein (pdb:2I9M) by standard molecular dynamics simulation (single trajectory) at room temperature with implicit solvent. Starting from a fully extended structure, 2I9M successfully folds into the native conformation within 16 ns using adaptive hydrogen bond-specific charges to take into account the electrostatic polarization effect. Cluster analysis shows that conformations in the native state cluster have the highest population (78.4%) among all sampled conformations. Folding snapshots and the secondary structure analysis demonstrate that the folding of 2I9M begins at terminals and progresses toward the center. A plot of the free energy landscape indicates that there is no significant free energy barrier during folding, which explains the observed fast folding speed. For comparison, exactly the same molecular dynamics simulation but carried out under existing AMBER charges failed to fold 2I9M into native-like structures. The current study demonstrates that electrostatic polarization of intraprotein hydrogen bonding, which stabilizes the helix, is critical to the successful folding of 2I9m.

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

“…And this charge fitting scheme is termed the AHBC scheme. 35 The AHBC has been successfully applied to folding simulation of a short peptide, and we showed that electrostatic polarization along the hydrogen bond can accelerate the formation of α-helix and increased the population of native structure during equilibrium. The detailed simulation condition can be found in the supplementary material.…”

Molecular dynamics simulation exploration of unfolding and refolding of a ten-amino acid miniprotein

“…Under some conditions, such as high temperature, extremes of pH or mechanical forces, protein will unfold into random coil that loses biochemical function (Selkoe 2003). Since folding and unfolding are essential to life, literatures on the study of these processes are very rich (Gao and Truhlar 2002;Gao et al 2006;Freddolino et al 2010;Yang et al 2010;Alhambra et al 2000;Duan et al 2010;Shank et al 2010). And it has been greatly advanced in recent years by the development of fast time-resolved techniques.…”

Folding of EK peptide and its dependence on salt concentration and pH: A computational study

“…Polarized atomic charges are obtained by periodic restrained fitting to electrostatic potential calculated at quantum mechanical level in continuum solvent [25]. As in our previous work [25], charge update is based on the main chain hydrogen bond variation to save the computational expense. In this regard, this charge scheme is termed AHBC.…”

“…Among various linear scaling quantum mechanical methods, the molecular fractionation with conjugate caps (MFCC) proposed in Zhang's group has been proved to be quite efficient for the electronic structure calculation for protein [15][16][17]. Recently, based on the MFCC method, a new charge scheme for protein termed the adaptive hydrogen bond-specific charge (AHBC) has been developed [25,26]. AHBC is obtained by periodic restrained fitting to the electrostatic potential (RESP) calculated usually at density functional theory (DFT) level in continuum solvent.…”

“…Thus AHBC is consistent with the AMBER force fields, and it can cooperate well with other AMBER force field parameters, like bond, angle and dihedral terms. Its applicability and advantage over traditional AMBER force field have been shown in several studies, including pK a prediction [26], structural stability [27,28], NMR coupling [29,30], protein/ligand binding [31] and peptide folding [25].…”