Conformation Dependence of Backbone Geometry in Proteins

Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.
Structure (Impact Factor: 5.62). 10/2009; 17(10):1316-25. DOI: 10.1016/j.str.2009.08.012
Source: PubMed


Protein structure determination and predictive modeling have long been guided by the paradigm that the peptide backbone has a single, context-independent ideal geometry. Both quantum-mechanics calculations and empirical analyses have shown this is an incorrect simplification in that backbone covalent geometry actually varies systematically as a function of the phi and Psi backbone dihedral angles. Here, we use a nonredundant set of ultrahigh-resolution protein structures to define these conformation-dependent variations. The trends have a rational, structural basis that can be explained by avoidance of atomic clashes or optimization of favorable electrostatic interactions. To facilitate adoption of this paradigm, we have created a conformation-dependent library of covalent bond lengths and bond angles and shown that it has improved accuracy over existing methods without any additional variables to optimize. Protein structures derived from crystallographic refinement and predictive modeling both stand to benefit from incorporation of the paradigm.

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    • "Thus unless the full form of the potential energy function is applied to minimise the energy, the accumulation of small deviations from equilibrium values may exert significant effects on inter-atomic separation, and hence solvent accessibility. An analogous argument applies concerning the use of context-independent average bond length and valence bond angle parameter values obtained from analyses of experimental structure databases in which distinct component conformation-dependent data distributions can remain hidden (Berkholz et al., 2009). The fixing of main-chain and side-chain proper dihedral angles to inappropriate or mutually incompatible combinations may also lead to poor estimates of maximal atomic solvent accessibility in reference state models, even when all other degrees of freedom have been optimised. "
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    ABSTRACT: Relative amino acid residue solvent accessibility values allow the quantitative comparison of atomic solvent-accessible surface areas in different residue types and physical environments in proteins and in protein structural alignments. Geometry-optimised tri-peptide structures in extended solvent-exposed reference conformations have been obtained for 43 amino acid residue types at a high level of quantum chemical theory. Significant increases in side-chain solvent accessibility, offset by reductions in mainchain atom solvent exposure, were observed for standard residue types in partially geometry-optimised structures when compared to non-minimised models built from identical sets of proper dihedral angles abstracted from the literature. Optimisation of proper dihedral angles led most notably to marked increases of up to 54% in proline main-chain atom solvent accessibility compared to literature values. Similar effects were observed for fully-optimised tri-peptides in implicit solvent. The relief of internal strain energy was associated with systematic variation in N, Ca and Cb atom solvent accessibility across all standard residue types. The results underline the importance of optimisation of ‘hard’ degrees of freedom (bond lengths and valence bond angles) and improper dihedral angle values from force field or other context-independent reference values, and impact on the use of standardised fixed internal co-ordinate geometry in sampling approaches to the determination of absolute values of protein amino acid residue solvent accessibility. Quantum chemical methods provide a useful and accurate alternative to molecular mechanics methods to perform energy minimisation of peptides containing non-standard (chemically modified) amino acid residues frequently present in experimental protein structure data sets, for which force field parameters may not be available. Reference tri-peptide atomic co-ordinate sets including hydrogen atoms are made freely available.
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    • "Despite the impressive successes of protein crystallography, the methodological aspects related to the inclusion of these parameters in the refinement are still highly debated [51]–[53]. Our results support the idea that the context dependence of stereochemistry should be introduced in the refinement procedures of protein structures in order to enhance model accuracy [52], [54], [55]. In addition, the correlations here detected may be used as a validation tool for protein structures [26], [56]. "
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