Naganathan Athi N.

Statistical mechanical models that afford an intermediate resolution between macroscopic chemical models and all-atom simulations have been successful in capturing folding behaviors of many small single-domain proteins. However, the applicability of one such successful approach, the Wako-Saitô-Muñoz-Eaton (WSME) model, is limited by the size of the protein as the number of conformations grows exponentially with protein length. In this work, we surmount this size limitation by introducing a novel approximation that treats stretches of 3 or 4 residues as blocks, thus reducing the phase space by nearly three orders of magnitude. The performance of the ‘bWSME’ model is validated by comparing the predictions for a globular enzyme (RNase H) and a repeat protein (IκBα), against experimental observables and the model without block approximation. Finally, as a proof of concept, we predict the free-energy surface of the 370-residue, multi-domain maltose binding protein and identify an intermediate in good agreement with single-molecule force-spectroscopy measurements. The bWSME model can thus be employed as a quantitative predictive tool to explore the conformational landscapes of large proteins, extract the structural features of putative intermediates, identify parallel folding paths, and thus aid in the interpretation of both ensemble and single-molecule experiments.

Deciphering the folding mechanism of small single-domain proteins has a long and well-chartered history that has been and still is aided by numerous experimental and computational approaches. The computational tools at the disposal of the folding community range from all-atom molecular simulations to structure-based models. In this review, we highlight one such structure-based statistical mechanical model termed the Wako-Saitô-Munõz-Eaton (WSME) model. We have, over the past few years, made the model physically more realistic by systematically introducing mean-field terms for solvation and electrostatics apart from conventional packing interactions. The WSME model can simply be calibrated with equilibrium unfolding curves and various features such as heat capacity thermograms, free-energy surfaces or profiles and hence the folding mechanism, changes in stability upon point mutations or certain post-translational modifications, thermodynamic vs. dynamic effects and possible connections with function fallout of the model without additional calibration. The model requires only a small set of tunable thermodynamic parameters (∼3-4) allowing for a tremendous scope in further improvement of its energy function. Most importantly, it can be employed as a rapid, physical and ensemble-based tool to directly characterize experimental equilibrium and kinetic rate and amplitude data (in real world units), that is not conventionally possible in other native-centric treatments. We believe that the WSME model is now poised to address numerous questions in the field of protein folding including pathway heterogeneity, structural-energetic relations, quantifying disorder and the effect of point mutations in disease.