CASP10-BCL::Fold efficiently samples topologies of large proteins

Abstract

During CASP10 in summer 2012, we tested BCL::Fold for prediction of free modeling (FM) and template-based modeling (TBM) targets. BCL::Fold assembles the tertiary structure of a protein from predicted secondary structure elements (SSEs) omitting more flexible loop regions early on. This approach enables the sampling of conformational space for larger proteins with more complex topologies. In preparation of CASP11, we analyzed the quality of CASP10 models throughout the prediction pipeline to understand BCL::Fold’s ability to sample the native topology, identify native-like models by scoring and/or clustering approaches, and our ability to add loop regions and side chains to initial SSE-only models. The standout observation is that BCL::Fold sampled topologies with a GDT_TS score > 33% for 12 of 18 and with a topology score > 0.8 for 11 of 18 test cases de novo. Despite the sampling success of BCL::Fold, significant challenges still exist in clustering and loop generation stages of the pipeline. The clustering approach employed for model selection often failed to identify the most native-like assembly of SSEs for further refinement and submission. It was also observed that for some β-strand proteins model refinement failed as β-strands were not properly aligned to form hydrogen bonds removing otherwise accurate models from the pool. Further, BCL::Fold samples frequently non-natural topologies that require loop regions to pass through the center of the protein.

Pushing the size limit of de novo structure ensemble prediction guided by sparse SDSL-EPR restraints to 200 residues: The monomeric and homodimeric forms of BAX

“…Therefore, this study represents a benchmark test if SDSL-EPR data are sufficient to determine the structure of biologically important states of large, membrane-associated proteins. BCL::Fold is tailored towards assembly of large protein structures from predicted secondary structure elements (SSEs) (Heinze et al, 2015; Karakaş et al, 2012). In a first step, the tertiary structure of soluble monomeric BAX was predicted from twenty-five SDSL-EPR distance restraints (Bleicken et al, 2014), demonstrating the feasibility of the protocol as well as the influence of the limited SDSL-EPR data on de novo protein structure prediction.…”

BCL::SAXS: GPU accelerated Debye method for computation of small angle X-ray scattering profiles

“…It computes complete SAXS scattering profiles for complete protein models and an approximate scattering profile for protein models that consist of secondary structure elements only as used in BCL::Fold. 23,24,26,27 The main methods to calculate a SAXS scattering profile from atomic coordinates are spherical harmonics with multipole expansion, Monte Carlo methods, and the Debye formula. 28-31 Multipole expansion methods have been shown to be highly accurate, but difficult to modify for incomplete protein models.…”

“…Here, we describe our newly developed algorithm BCL::SAXS. It computes complete SAXS scattering profiles for complete protein models and an approximate scattering profile for protein models that consist of secondary structure elements only as used in BCL::Fold . The main methods to calculate a SAXS scattering profile from atomic coordinates are spherical harmonics with multipole expansion, Monte Carlo methods, and the Debye formula .…”

CASP11 – An Evaluation of a Modular BCL::Fold-Based Protein Structure Prediction Pipeline

“…The energy evaluation of the sampled models is conducted using knowledge-based scoring functions [ 7 ], which provide a rapid way to approximate the free energy of the sampled conformation. In a previous study, it was demonstrated that BCL::Fold is able to efficiently sample the topologies of larger proteins [ 8 ]. Problems in model discrimination, which can arise from necessary simplifications made to sampling, scoring, and system representation, can be compensated for through incorporation of limited experimental data from electron microscopy [ 9 – 11 ], nuclear magnetic resonance spectroscopy [ 12 ], electron paramagnetic resonance spectroscopy [ 13 , 14 ], cross-linking experiments [ 15 ], small angle X-ray and neutron scattering [ 16 ], and predicted residue-residue contacts.…”