Accurate ab Initio Study on the Hydrogen-Bond Pairs in Protein Secondary Structures

Abstract

Ab initio calculations up to the MP2/aug-cc-pVQZ//MP2/6-311+G** level have been carried out to characterize the four patterns of hydrogen-bond (H-bond) pairs in protein secondary structures. The unblocked and methyl-blocked glycine dipeptide dimers were arranged to model the H-bond pairs in α-helix (αHH) and antiparallel (Aββ-C 5 and Aββ-C 7 ) and parallel β-sheet (Pββ) secondary structures. The study uncovers that, in addition to the primary CO⋯NH H-bonds and the crossing secondary interactions, the CH⋯OC H-bonds and the tertiary effect (as we call it) also contribute substantially. The tertiary effect is due to the interpolarization between the donor and acceptor of a H-bond. This effect, which enhances the dipole-dipole interactions between two nearby H-bonds, stabilizes the β-sheet-like but destabilizes the helix-like H-bond pairs. The MP2 binding energies of the complexes were further refined by extrapolating to the complete basis set limit (CBS) according to Truhlar and co-workers and by a three-basis-set-based method. The best extrapolated CBS(aD-aT-aQ) binding energies of the unblocked dimers are −13.1 (αHH), −11.3 (Aββ-C 5 ), −19.2 (Aββ-C 7 ), and −14.8 kcal/mol (Pββ). For the methyl-blocked counterparts, the best extrapolated CBS(D-T-Q) binding energies are −14.8, −13.4, −20.8, and −16.7 kcal/mol, respectively. The interactions in the parallel β conformations are very close to the averages of the C 5 and C 7 antiparallel β conformations, and both are stronger than the helical dimers. Because the additive force fields are unable to account for the tertiary effect owing to the lack of polarization, all examined additive force fields significantly overestimate the interaction energies of the helix conformations relative to the β-sheet conformations. Notably, the agreement between molecular mechanical and quantum mechanical binding energies is improved after turning on the polarization. The study provides reference ab initio structures and binding energies for characterizing the backbone H-bonds of the protein secondary structures, which can be used for the parametrization of empirical molecular mechanics force fields.

Investigation on the individual contributions of NH···OC and CH···OC interactions to the binding energies of β‐sheet models

“…17 Besides of C a À ÀHÁÁÁO¼ ¼C interactions and the secondary electrostatic interaction, Duan further suggested the tertiary effect also contribute to the difference, which enhances the dipole-dipole interactions between two nearby hydrogen bonds. 27 We use the first term of eq. (1) For the parallel diglypeptide dimer corresponding to the formation of MR (dimer 3), Table 3 shows that the total of the two NÀ ÀHÁÁÁO¼ ¼C attractive interactions is 211.56 kcal/mol, the total of the two C a À ÀHÁÁÁO¼ ¼C attractive interactions is 23.06 kcal/ mol, the summation of the attractive interactions is 214.62 kcal/ mol.…”

“…14,15 Currently, there are intense research efforts to understand the stability and dynamic features of b-sheet formation. [16][17][18][19][20][21][22][23][24][25][26][27] Wu has suggested cooperativity in both a-and 3 10 -helices 28 and in sheets of unnatural b-polyglycines 29 but little or none in b-sheets of the natural a-polyglycines. 16 Dannenberg also confirmed that the association of polyglycine strands shows little or no hydrogen bond cooperativity.…”

Evaluation of the individual hydrogen bonding energies in N-methylacetamide chains

“…Liu et al concluded that the charge flow between the hydrogen bond donor and acceptor groups in the cis-NMF molecule is the most significant factor inducing the cooperative effect of a hydrogen bond [14]. Wang et al evaluated the hydrogen bond pairs in protein secondary structures, which provided reference ab initio structures and binding energies for characterizing the backbone hydrogen bonds of the protein secondary structures [15]. It was found that due to the difficulty of forming three optimal hydrogen bonds between two rigid molecules, the energy contribution for guanine-cytosine is weaker than that for adenine-thymine [16].…”

“…Although many investigations have been carried out to study the NH···O=C hydrogen bonding strength [6,12,15,[19][20][21] in biosystems, the individual hydrogen bonding energies for complex biosystems have not been studied in detail. The individual NH···O=C hydrogen bonding energies are significant in understanding the conformation stability of peptides and proteins.…”

Theoretical studies on the binding energy of β-sheet models

“…The importance of β-sheet interactions in biological processes makes them potential targets for intervention in diseases such as AIDS and other cancer. Currently, intensive research efforts have been made to understand the stability and dynamic features of β-sheets formation [2][3][4][5][6][7] . It has been found that several diseases, such as Alzheimer's disease, mad-cow disease, Creutzfeldt-Jakob, and other neurodegenerative disorders, are associated with the formation of β-sheet peptides [8][9][10][11][12] .…”