An official website of the United States government
Flory’s random coil model assumes that conformational fluctuations of amino acid residues in unfolded poly(oligo)peptides and proteins are uncorrelated (isolated pair hypothesis, IPH). This implies that conformational energies, entropies and solvation free energies are all additive. Nearly 25 years ago, analyses of coil libraries cast some doubt on this notion, in that they revealed that aromatic, but also β-branched side chains, could change the 3J(HNHCα) coupling of their neighbors. Since then, multiple bioinformatical, computational and experimental studies have revealed that conformational propensities of amino acids in unfolded peptides and proteins depend on their nearest neighbors. We used recently reported and newly obtained Ramachandran plots of tetra- and pentapeptides with non-terminal homo- and heterosequences of amino acid residues to quantitatively determine nearest neighbor coupling between them with a Ising type model. Results reveal that, depending on the choice of amino acid residue pairs, nearest neighbor interactions either stabilize or destabilize pairs of polyproline II and β-strand conformations. This leads to a redistribution of population between these conformations and a reduction in conformational entropy. Interactions between residues in polyproline II and turn(helix)-forming conformations seem to be cooperative in most cases, but the respective interaction parameters are subject to large statistical errors.
more »
« less
A new interpretation of the structure and solvent dependence of the far UV circular dichroism spectrum of short oligopeptides
UV circular dichroism (UVCD) spectroscopy is a prominent tool for exploring secondary structures of polypeptides and proteins. In the unfolded state of these biomolecules, most of the individual residues primarily sample a conformation called polyproline II. Its CD spectrum contains a negatively biased positive couplet with a pronounced negative maximum below and a weak positive maximum above 200 nm. It is traditionally rationalized in terms of an excitonic coupling mechanism augmented by polarization effects. In this work, we carry out new time-dependent density functional theory calculations on the cationic tripeptide GAG in implicit and explicit water to determine the transitions that give rise to the observed CD signals of polyproline II and β-strand conformations. Our results reveal a plethora of electronic transitions that are governed by configurational interactions between multiple molecular orbital transitions of comparable energy. We also show that reproducing the CD spectra of polyproline II and β-strand conformations requires the explicit consideration of water molecules. The structure dependence of delocalized occupied orbitals contributes to the experimentally-observed invalidation of Flory's isolated pair hypothesis.
more »
« less
- Award ID(s):
- 1707770
- PAR ID:
- 10094390
- Date Published:
- Journal Name:
- Chemical Communications
- Volume:
- 55
- Issue:
- 40
- ISSN:
- 1359-7345
- Page Range / eLocation ID:
- 5701 to 5704
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Molecular dynamics (MD) is a powerful tool for studying intrinsically disordered proteins, however, its reliability depends on the accuracy of the force field. We assess Amber ff19SB, Amber ff14SB, OPLS-AA/M, and CHARMM36m with respect to their capacity to capture intrinsic conformational dynamics of 14 guest residues x (=G, A, L, V, I, F, Y, D P , E P , R, C, N, S, T) in GxG peptides in water. The MD-derived Ramachandran distribution of each guest residue is used to calculate 5 J-coupling constants and amide I′ band profiles to facilitate a comparison to spectroscopic data through reduced χ 2 functions. We show that the Gaussian model, optimized to best fit the experimental data, outperforms all MD force fields by an order of magnitude. The weaknesses of the MD force fields are: (i) insufficient variability of the polyproline II (pPII) population among the guest residues; (ii) oversampling of antiparallel at the expense of transitional β-strand region; (iii) inadequate sampling of turn-forming conformations for ionizable and polar residues; and (iv) insufficient guest residue-specificity of the Ramachandran distributions. Whereas Amber ff19SB performs worse than the other three force fields with respect to χ 2 values, it accounts for residue-specific pPII content better than the other three force fields. Additional testing of residue-specific RSFF1 and Amber ff14SB combined with TIP4P/2005 on six guest residues x (=A, I, F, D P , R, S) reveals that residue specificity derived from protein coil libraries or an improved water model alone do not result in significantly lower χ 2 values.more » « less
-
n→π* interactions between consecutive carbonyls stabilize the α-helix and polyproline II helix (PPII) conformations in proteins. n→π* interactions have been suggested to provide significant conformational biases to the disordered states of proteins. To understand the roles of solvation on the strength of n→π* interactions, computational investigations were conducted on a model n→π* interaction, the twisted-parallel-offset formaldehyde dimer, as a function of explicit solvation of the donor and acceptor carbonyls, using water and HF. In addition, the effects of urea, thiourea, guanidinium, and monovalent cations on n→π* interaction strength were examined. Solvation of the acceptor carbonyl significantly strengthens the n→π* interaction, while solvation of the donor carbonyl only modestly weakens the n→π* interaction. The n→π* interaction strength was maximized with two solvent molecules on the acceptor carbonyl. Urea stabilized the n→π* interaction via simultaneous engagement of both oxygen lone pairs on the acceptor carbonyl. Solvent effects were further investigated in the model peptides Ac-Pro-NMe 2 , Ac-Ala-NMe 2 , and Ac-Pro 2 -NMe 2 . Solvent effects in peptides were similar to those in the formaldehyde dimer, with solvation of the acceptor carbonyl increasing n→π* interaction strength and resulting in more compact conformations, in both the proline endo and exo ring puckers, as well as a reduction in the energy difference between these ring puckers. Carbonyl solvation leads to an energetic preference for PPII over both the α-helix and β/extended conformations, consistent with experimental data that protic solvents and protein denaturants both promote PPII. Solvation of the acceptor carbonyl weakens the intraresidue C5 hydrogen bond that stabilizes the β conformation.more » « less
-
null (Ed.)Abstract Regulatory protein access to the DNA duplex ‘interior’ depends on local DNA ‘breathing’ fluctuations, and the most fundamental of these are thermally-driven base stacking-unstacking interactions. The smallest DNA unit that can undergo such transitions is the dinucleotide, whose structural and dynamic properties are dominated by stacking, while the ion condensation, cooperative stacking and inter-base hydrogen-bonding present in duplex DNA are not involved. We use dApdA to study stacking-unstacking at the dinucleotide level because the fluctuations observed are likely to resemble those of larger DNA molecules, but in the absence of constraints introduced by cooperativity are likely to be more pronounced, and thus more accessible to measurement. We study these fluctuations with a combination of Molecular Dynamics simulations on the microsecond timescale and Markov State Model analyses, and validate our results by calculations of circular dichroism (CD) spectra, with results that agree well with the experimental spectra. Our analyses show that the CD spectrum of dApdA is defined by two distinct chiral conformations that correspond, respectively, to a Watson–Crick form and a hybrid form with one base in a Hoogsteen configuration. We find also that ionic structure and water orientation around dApdA play important roles in controlling its breathing fluctuations.more » « less
-
Short chain perfluoroalkyl substances (PFAS), replacements for long chain legacy PFAS such as perfluorooctanoic acid (PFOA), have similar toxicity, negative health effects, and exceptional persistence as long chain PFAS. β-Cyclodextrin (β-CD) is a powerful host–guest complexing agent for a number of legacy PFAS, suggesting potential β-CD-based remediation processes. We report herein that the addition of charged functional groups at the perimeter of β-CD has a pronounced influence on the strength of the β-CD:PFAS complex. The presence of a positively charged amine functionality on the perimeter of β-CD significantly increases the complexation of legacy and short chain PFAS. We assigned the enhanced complexation to electrostatic attraction between the negatively charged PFAS head group and the positively charged β-CD derivative. In comparison to neutral β-CD, addition of a negative charge to β-CD decreases complexation to PFAS due to electrostatic repulsion between the negatively charged polar head group of PFAS and the negatively charged β-CD. 19F NMR titration experiments illustrate the complexation of short chain PFAS by positive charged β-CDs over neutral β-CD, with increases up to 20 times depending on the PFAS guest. The results give further understanding to the nature of the β-CD:PFAS host–guest complex and the various intermolecular forces that drive complexation. Positively charged β-CDs appear to be potential complexing agents for remediation of short chain PFAS.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/c9cc01513b
