A set of representative hydrogen bonded dimers has been studied employing density functional theory (DFT) in the Perdew, Burke, and Ernzerhof (PBE) generalized gradient approximation. Our results for hydrogen bond (hb) strengths and geometry parameters show good agreement with those obtained by Møller-Plesset (MP2) or Coupled-Cluster (CC) methods. We observe that the reliability of DFT-PBE for the description of hbs is closely connected to the bond directionality (i.e. the angle between D-H and H‚‚‚A where D and A are the donor and the acceptor atoms or regions, respectively, in the hb interaction): with increasing deviation from a linear D-H‚‚‚A arrangement the accuracy of the DFT-PBE decreases.

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...

We studied the energetics of finite and infinite polyalanine chains in the α-helical and extended structure by employing density-functional theory. On the basis of these results we extracted the energy of hydrogen bonds (hb's) and their interactions by taking the full peptide−peptide connectivity (backbone) of proteins into account. We focus on two limiting cases:  an isolated hb and one within an infinite α-helical chain. In the infinite chain the cooperativity within an infinite network of hb's strengthens each individual bond by more than a factor of 2. This effect has important consequences for the stability of α-helices.

We analyzed the response to strain of an infinite polyalanine chain in the alpha-helical conformation using density functional theory. Under compressive strain the alpha-helix is found to undergo structural transitions to a pi-helix when the length of the helix is reduced by more than 10%. Under tensile strain the structure changes into a 3(10)-helix when the length is stretched by more than 10%. Our analysis of these transitions shows that they proceed essentially in two steps: At first there is mainly a length change, and only with some delay the helix twist adjusts.