Template-Guided Protein Structure Prediction and Using Optimized Folding Landscape Force Fields

MC Chen and XC Lin and W Lu and NP Schafer and JN Onuchic and PG Wolynes, JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 14, 6102-6116 (2018).

DOI: 10.1021/acs.jctc.8b00683

When good structural templates can be identified, template-based modeling is the most reliable way to predict the tertiary structure of proteins. In this study, we combine template-based modeling with a realistic coarse-grained force field, AWSEM, that has been optimized using the principles of energy landscape theory. The Associative memory, Water mediated, Structure and Energy Model (AWSEM) is a coarse-grained force field having both transferable tertiary interactions and knowledge-based local-in-sequence interaction terms. We incorporate template information into AWSEM by introducing soft collective biases to the template structures, resulting in a model that we call AWSEM- Template. Structure prediction tests on eight targets, four of which are in the low sequence identity "twilight zone" of homology modeling, show that AWSEM-Template can achieve high-resolution structure prediction. Our results also confirm that using a combination of AWSEM and a template-guided potential leads to more accurate prediction of protein structures than simply using a template guided potential alone. Free energy profile analyses demonstrate that the soft collective biases to the template effectively increase funneling toward native-like structures while still allowing significant flexibility so as to allow for correction of discrepancies between the target structure and the template. A further stage of refinement using all-atom molecular dynamics augmented with soft collective biases to the structures predicted by AWSEM-Template leads to a further improvement of both backbone and side-chain accuracy by maintaining sufficient flexibility but at the same time discouraging unproductive unfolding events often seen in unrestrained all-atom refinement simulations. The all-atom refinement simulations also reduce patches of frustration of the initial predictions. Some of the backbones found among the structures produced during the initial coarse grained prediction step already have CE-RMSD values of less than 3 angstrom with 90% or more of the residues aligned to the experimentally solved structure for all targets. All-atom structures generated during the following all-atom refinement simulations, which started from coarse-grained structures that were chosen without reference to any knowledge about the native structure, have CE-RMSD values of less than 2.5 angstrom with 90% or more of the residues aligned for 6 out of 8 targets. Clustering low energy structures generated during the initial coarse-grained annealing picks out reliably structures that are within 1 angstrom of the best sampled structures in 5 out of 8 cases. After the all-atom refinement, structures that are within 1 angstrom of the best sampled structures can be selected using a simple algorithm based on energetic features alone in 7 out of 8 cases.

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