Energetics of Protein Folding

Baldwin, Robert L.

doi:10.1016/j.jmb.2007.05.078

Cited by 263 publications

(264 citation statements)

References 118 publications

(171 reference statements)

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“…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 form helical structures [11], and its widespread use as a benchmark system for peptide stability in experiment [12][13][14][15] and in theory (see, e.g., Refs. [16][17][18][19][20][21][22][23][24] and references therein).…”

mentioning

confidence: 99%

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

et al. 2011

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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...

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confidence: 99%

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

et al. 2011

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“…However the laboratory determined coefficients are compromised by the known fact that n-octanol contains ~2.3 M of water. Other solvents have been suggested to better represent the interior of proteins, including cyclohexane, 1,9 decadiene, and n-octane [41][42][43][44][45]. Partition co-efficients of a non-polar solute (log S) or an ionized solute (log D) between water and n-octanol are experimentally determined, and the free energy, enthalpy and entropy can be determined by isothermal calorimetry.…”

Section: δE Int = δE Hydrophilic + δE Hydrophobic (Water)mentioning

confidence: 99%

“…However the free energy contribution per unit area buried was only about 30-50% of previous similar studies of transfer free energies of small ligands. The transfer of an ion from water to a nonpolar media with dielectric constant of ~3 (lipid bilayer) or 4 to 10 (interior of proteins) costs significant energy [40,41].…”

Section: δE Int = δE Hydrophilic + δE Hydrophobic (Water)mentioning

confidence: 99%

Binding energies of tyrosine kinase inhibitors: Error assessment of computational methods for imatinib and nilotinib binding

Fong¹

2015

Computational Biology and Chemistry

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To cite this version:Clifford Fong. Binding Energies of Tyrosine Kinase Inhibitors: error assessment of computational methods for imatinib and nilotinib binding. Computational Biology and Chemistry, Elsevier, 2015, 58, pp.40-54. <10.1016/j.compbiolchem.2015 The binding energies of imatinib and nilotinib to tyrosine kinase have been determined by quantum mechanical (QM) computations, and compared with literature binding energy studies using molecular mechanics (MM). The potential errors in the computational methods include these critical factors: Errors in X-ray structures such as structural distortions and steric clashes give unrealistically high van der Waals energies, and erroneous binding energies.  MM optimisation gives a very different configuration to the QM optimisation for nilotinib, whereas the imatinib ion gives similar configurations  Solvation energies are a major component of the overall binding energy. The QM based solvent model (PCM/SMD) gives different values from those used in the implicit PBSA solvent MM models. A major error in inhibitor -kinase binding lies in the non-polar solvation terms.  Solvent transfer free energies and the required empirical solvent accessible surface area factors for nilotinib and imatinib ion to give the transfer free energies have been reverse calculated. These values differ from those used in the MM PBSA studies.  An intertwined desolvation -conformational binding selectivity process is a balance of thermodynamic desolvation and intramolecular conformational kinetic control.  The configurational entropies (TΔS) are minor error sources.

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“…Much has been learnt about protein folding (Baldwin 2007;Rose et al 2006) and much accomplished in its implementation in de novo design (Allen and Mayo 2010;Baker 2010;Korendovych et al 2010). The time is therefore ripe to explore excursions with Nature's design algorithm beyond the realm of biological alphabets.…”

Section: De Novo Design Of Hetero-chiral Proteinsmentioning

confidence: 99%