Topology‐based models and NMR structures in protein folding simulations

Abstract

Topology-based interaction potentials are simplified models that use the native contacts in the folded structure of a protein to define an energetically unfrustrated folding funnel. They have been widely used to analyze the folding transition and pathways of different proteins through computer simulations. Obviously, they need a reliable, experimentally determined folded structure to define the model interactions. In structures elucidated through NMR spectroscopy, a complex treatment of the raw experimental data usually provides a series of models, a set of different conformations compatible with the available experimental data. Here, we use an efficient coarse-grained simulation technique to independently consider the contact maps from every different NMR model in a protein whose structure has been resolved by the use of NMR spectroscopy. For lambda-Cro repressor, a homodimeric protein, we have analyzed its folding characteristics with a topology-based model. We have focused on the competition between the folding of the individual chains and their binding to form the final quaternary structure. From 20 different NMR models, we find a predominant three-state folding behavior, in agreement with experimental data on the folding pathway for this protein. Individual NMR models, however, show distinct characteristics, which are analyzed both at the level of the interplay between tertiary/quaternary structure formation and also regarding the thermal stability of the tertiary structure of every individual chain.

Topological Frustration in βα-Repeat Proteins: Sequence Diversity Modulates the Conserved Folding Mechanisms of α/β/α Sandwich Proteins

“…The Gō-model assigned an average of 1.2/1.1 (NT-NtrC) and 1.6/1.3 (Spo0F) native contacts per residue in the N-/C-subdomains, respectively. The lower average number of contacts for NT-NtrC compared to Spo0F reflects the limitations of the solution NMR structure for NT-NtrC compared to the crystal structures for Spo0F and CheY 46,47. The smaller number of native contact potentials to promote folding for NT-NtrC results in a lower energy barrier between the unfolded and folded basins than in the case of Spo0F (Fig.…”

Insights from Coarse-Grained Gō Models for Protein Folding and Dynamics

“…A common means to safeguard against this is to compare folding results for multiple proteins obtained using the same model in light of available experimental data. Simulation results can also be influenced by the experimental structure from which the Gō model is derived, particularly the method used in its solution [ 137 , 138 ]. Note that NtrC exhibits a lower folding barrier than CheY and Spo0F in Figure 1 , a result of having fewer native contacts overall and therefore a smoother landscape.…”

The folding space of protein β2-microglobulin is modulated by a single disulfide bridge

“…Since the Gō model is native-centric, it is natural to expect that simulated folding behaviour may be sensitive to the exact set of atomic coordinates that define the native structure. This question was originally addressed by Rey and co-workers in the context of a C α representation [38], [39], and later explored by one of us in the context of a full atomistic representation [19]. In the present work we explored the impact on folding of a particular aspect of the native structure of protein β2m, which is the existence of a SS-bond between residues 25 and 80.…”