Unraveling the Stability of Polypeptide Helices: Critical Role of van der Waals Interactions

Abstract

Folding and unfolding processes are important for the functional capability of polypeptides and proteins. In contrast with a physiological environment (solvated or condensed phases), an in vacuo study provides well-defined ''clean room'' conditions to analyze the intramolecular interactions that largely control the structure, stability, and folding or unfolding dynamics. Here we show that a proper consideration of van der Waals (vdW) dispersion forces in density-functional theory (DFT) is essential, and a recently developed DFT þ vdW approach enables long time-scale ab initio molecular dynamics simulations at an accuracy close to ''gold standard'' quantum-chemical calculations. The results show that the inclusion of vdW interactions qualitatively changes the conformational landscape of alanine polypeptides, and greatly enhances the thermal stability of helical structures, in agreement with gas-phase experiments. The helical motif is a ubiquitous conformation of amino acids in protein structures, and helix formation is a fundamental step of the protein folding process [1][2][3]. Simulations of helix formation and stability are typically carried out in solvent or condensed phases using classical, empirical ''force fields.'' However, different force field parameterizations lead to reliable results only for a narrow class of systems and conditions. A truly bottom-up understanding of polypeptide structure and dynamics would greatly benefit from a first-principles quantum-mechanical treatment, as it becomes increasingly more feasible for large systems and long time scales. In particular, quantum-mechanical simulations in vacuo are invaluable for a quantitative understanding of the intramolecular forces that largely control the structure, stability and (un) folding dynamics of polypeptides.Recent progress in the experimental isolation and spectroscopies of gas-phase biological molecules has lead to increasingly refined vibrational spectra for the structure of peptides and proteins [4][5][6]. In fact, in vacuo proteins frequently preserve the secondary structure (helices and sheets) observed in solution, and recent results [7] have shown that even tertiary and quaternary structures can be transferred into the gas phase. Joint experimental and ab initio theoretical studies can now successfully determine the geometries of small gas-phase peptides [8][9][10]. Nevertheless, many fundamental questions remain open, such as: (1) How stable is the folded polypeptide helix in comparison to other (meta)-stable structures? (2) How important are the different enthalpic and entropic contributions to the stability of helical conformations? Here we provide quantitative insight into the above two questions from first principles for the fundamental case of polyalanine helices in vacuo. Our study reveals the crucial role that van der Waals (vdW) interactions play for the helix stability and dynamics, illustrating how entropy is significantly altered as well. We choose polyalanine as a target for our study due to its high propensity to fo...

First-Principles Models for van der Waals Interactions in Molecules and Materials: Concepts, Theory, and Applications

“…102,335−338 In a recent AIMD study, 334 it was shown that the inclusion of vdW forces can explain the notable stability of polyalanine (Ac-Ala n -LysH + ) helices up to a temperature of 725 K. 339 Figure 12 illustrates the fact that AIMD simulations at the PBE and PBE+TS levels of theory paint very different pictures of the dynamical helix structure over a wide range of temperatures. For instance, AIMD simulations at 700 K with PBE+TS give a structure that is comprised of both α and 3 10 -helical motifs with an overall helical structure that is preserved after 65 ps of simulation, whereas PBE predicts that the α-helical motifs quickly disappear within 5−7 ps, in contradiction to the experimental evidence.…”

Contribution of the empirical dispersion correction on the conformation of short alanine peptides obtained by gas-phase QM calculations

“…5–9 Moreover, advances in computer technology have allowed researchers to perform calculations with progressively larger basis sets and higher levels of theory. 10–12 Earlier work 10,11,13–15 shows that the inclusion of electron correlation in QM calculations affects to different degrees the conformational propensity of small peptides and the stability of helical motifs. Accounting for electron correlation in an approximate fashion, less computationally expensive methods based on density functional theory (DFT) have often provided a speedy and reliable description of the conformational energy of minimal peptide models.…”

Role of methyl-induced polarization in ion binding

“…The primary challenge associated with investigating these issues is to model accurately the broad range of molecular forces involved in ion complexation, in particular, polarization and dispersion, which contribute nontrivially to ion-ligand and ligandligand energetics (23)(24)(25). A consistent first-principles approach is therefore essential.…”