Article

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

ABSTRACT

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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    • "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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