Results: 2

1.
Figure 1

Figure 1. From: Synonymous Mutations and Ribosome Stalling Can Lead to Altered Folding Pathways and Distinct Minima.

Simplified folding free energy landscape to illustrate two types of protein folding pattern scenarios. At the single molecule level, the native protein conformation is more favorable thermodynamically than the altered conformation due to synonymous mutations (Figure 1A). However, the folding free energy shifts toward favoring the haplotype conformation at high concentration with a portion of the conformation changed significantly due to inter-molecular association. The sizable barrier in Figure 1A reflects the involvement of a significant conformational change. Figure 1B illustrates the second type of folding pattern. At the bottom of the folding funnel, the landscape is rugged with many local minima, each representing a similar but distinct core structure. The intermediate barrier in the Figure 1B is to emphasize that there is only a minor conformational change when moving from one local minimum to the other. Unlike the first (amyloid) folding pattern, here the folding free energy landscape will not change since it does not involve inter-molecular interactions. The final folded conformation is mainly controlled by folding kinetics: a different folding pathway leads to a different conformation.

Chung-Jung Tsai, et al. J Mol Biol. ;383(2):281-291.
2.
Figure 2

Figure 2. From: Synonymous Mutations and Ribosome Stalling Can Lead to Altered Folding Pathways and Distinct Minima.

A simple scheme to illustrate the origin of a minor conformational change via a ribosome stalling effect. Along a sequence, say at an arbitrary position S1, fragment A preceding S1 is a slow folder and the fragment B following S1 folds faster than fragment A. Also, fragment A has two competing conformations, A1 and A2 with A2 more stable than A1 by itself but A1 becomes more favorable in the presence of fragment B. Let us assume that the folding of the nascent chain is independent. Then the folding landscape will be exactly the same for both the wild sequence (W) and the sequence (S) with a synonymous mutation at S1 since they have the same amino acid sequence. The co-translational folding pathway is expected to be identical up to the S1 position. In Figure 2A the folding pathways are drawn as step-by-step arrows on the simplified folding funnel surface. Without a pause at S1, fragment B folds before fragment A; then fragment A folds on fragment B with an A1 conformation. On the other hand, for the synonymous mutation at S1 case, the pause enables A2 to fold first and fragment B follows. The folding branches due to a pause in a sequential folding eventually lead to the bottom of funnel with minor conformational change between them. Figure 2B provides a diagram of the two folding scenarios.

Chung-Jung Tsai, et al. J Mol Biol. ;383(2):281-291.

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