Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization

Abstract

Most protein structural prediction algorithms assemble structures as reduced models that represent amino acids by a reduced number of atoms to speed up the conformational search. Building accurate full-atom models from these reduced models is a necessary step toward a detailed function analysis. However, it is difficult to ensure that the atomic models retain the desired global topology while maintaining a sound local atomic geometry because the reduced models often have unphysical local distortions. To address this issue, we developed a new program, called ModRefiner, to construct and refine protein structures from Cα traces based on a two-step, atomic-level energy minimization. The main-chain structures are first constructed from initial Cα traces and the side-chain rotamers are then refined together with the backbone atoms with the use of a composite physics- and knowledge-based force field. We tested the method by performing an atomic structure refinement of 261 proteins with the initial models constructed from both ab initio and template-based structure assemblies. Compared with other state-of-art programs, ModRefiner shows improvements in both global and local structures, which have more accurate side-chain positions, better hydrogen-bonding networks, and fewer atomic overlaps. ModRefiner is freely available at http://zhanglab.ccmb.med.umich.edu/ModRefiner.

Figure 1

Flowchart of the ModRefiner two-step full-atom model construction and refinement procedure.

Figure 2

Addition of N and C atoms based on four consecutive Cα atoms. (a) The definition of two inner angles and one torsion angle calculated from the four Cα atoms. (b) Adding one C atom from three consecutive Cα atoms with three parameters (distance, inner angle, and torsion angle). (c) Adding one N atom from three consecutive Cα atoms with three parameters (distance, inner angle, and torsion angle).

Figure 3

Illustration of movements used for the main-chain simulation (a–g) and full-atomic simulation (a–i). New positions of atoms after movements are connected by dash lines. New residue numbers after the shift in g are in italic type.

Figure 4

Example of ModRefiner in atomic structure construction and refinement from Cα trace. (a) Initial Cα trace, which is the cluster center generated by SPICKER. (b) Initial main-chain model. (c) Initial full-atom model after side-chain addition to the refined main-chain model. (d) Refined full-atom model by ModRefiner. (e) Native structure of 1obxA.

Figure 5

Comparison of the ModRefiner model (green) and initial model (red), both of which are superimposed on the native structure (blue). (a) Initial model from Rosetta prediction. (b) Initial model from I-TASSER prediction. (c) Local side-chain comparison of the three models in panel a. (d) Local side-chain comparison of the three models in panel b.