Modeling the Conformation of Side Chains in Proteins: Approaches, Problems and Possible Developments

Abstract

Simulation of the correct side chain conformations of amino acid residues is an intriguing issue not only for computational biology, but also for practical outcomes in biotechnology and medicine. This is also a main challenge for molecular simulations, since even in the homology modelling strategy (which uses templates to predict the unknown structure of a protein), the conformation of a side chain generally cannot be easily deduced from the structure of the template. It is important also for applications such as molecular design and docking. Moreover, the correct simulation of the effects of amino acid mutations occurring in many genetic diseases may help in understanding the molecular mechanisms that underlie those pathologies.This review aims to summarize the different strategies developed to predict side chain conformations in proteins. In the current review, differences in approaches are discussed and problems are analyzed, as well as parameters and criteria to compare and evaluate performances of the programs.

Adapting Poisson-Boltzmann to the self-consistent mean field theory: Application to protein side-chain modeling

“…Side chains in the core of a protein form a tight jigsaw puzzle, mostly controlled by steric effects and charge attractions and repulsions; as such, most methods that use a potential based on a Lennard-Jones potential for van der Waals (vdW) effects and a Coulomb potential for electrostatics perform well on buried side chains. 14 It should be noted that the way these potentials are implemented matters: for example, Mendes et al managed to obtain better performance with our SCMF method by simply scaling the 1-4 interactions. 19 The quality of the predictive power of side-chain prediction methods decreases significantly, however, for surface residues: this is usually understood as the inability of the energy function to account for the solvent and ion atmosphere around the protein.…”