Automated minimization of steric clashes in protein structures

Abstract

Molecular modeling of proteins including homology modeling, structure determination, and knowledge-based protein design requires tools to evaluate and refine three-dimensional protein structures. Steric clash is one of the artifacts prevalent in low-resolution structures and homology models. Steric clashes arise due to the unnatural overlap of any two non-bonding atoms in a protein structure. Usually, removal of severe steric clashes in some structures is challenging since many existing refinement programs do not accept structures with severe steric clashes. Here, we present a quantitative approach of identifying steric clashes in proteins by defining clashes based on the Van der Waals repulsion energy of the clashing atoms. We also define a metric for quantitative estimation of the severity of clashes in proteins by performing statistical analysis of clashes in high-resolution protein structures. We describe a rapid, automated and robust protocol, Chiron, which efficiently resolves severe clashes in low-resolution structures and homology models with minimal perturbation in the protein backbone. Benchmark studies highlight the efficiency and robustness of Chiron compared to other widely used methods. We provide Chiron as an automated web server to evaluate and resolve clashes in protein structures that can be further used for more accurate protein design.

MDA5 assembles into a polar helical filament on dsRNA

“…A filament model with five MDA5 molecules was refined with Situs (30) to iteratively refine domain positions and impose helical symmetry. The energy of the model was then minimized with Chiron (31).…”

Homology Modeling: Generating Structural Models to Understand Protein Function and Mechanism

“…Homology models on an average feature much higher extent of steric clashes when compared to experimental structures (a). The distribution of clashscores (which is a normalized energetic parameter reflecting the extent of steric clashes in a protein structure [50]) of high-resolution crystal structures and representative homology models from SWISS-MODEL database are plotted. The efficacy of Chiron in minimizing clashes in protein structure is demonstrated for the homology model of Q13823, whose initial model (b) has a clash-ratio of 0.13, much higher than that seen in experimental structures.…”

“…Tools such as MMTSB [48] and PULCHRA [49] have emerged for structure refinement, which includes removal of clashes during refinement. Chiron [50], an automated server evaluates the extent of clashes in a given structure and if required, minimizes these clashes to the levels seen in high-resolution X-ray structures. Chiron uses all-atom DMD [46,51] with soft-core potentials.…”

“…All these measures ensure that the covalent geometry of the structural model is physically acceptable. The packing quality can be assessed based on the extent of steric clashes [50], the prevalence of voids, and the scaling of the solvent accessible surface area with protein length [62]. There are several servers that can compare these structural parameters of a model with benchmark distribution to indicate the areas of the protein structure that need further refinement to be physically acceptable [61,62,64,65].…”

Tyrosine phosphorylation switching of a G protein

“…For each system, energy minimization was performed according to the protocol implemented in Chiron (71). Systems were then equilibrated by linearly increasing the simulation temperature from 0.1 to 0.45 kcal mol -1 kB -1 over 100,000 steps of discrete molecular dynamics (DMD) (72,73).…”