How does a simplified-sequence protein fold?
نویسندگان
چکیده
To investigate a putatively primordial protein we have simplified the sequence of a 56-residue alpha/beta fold (the immunoglobulin-binding domain of protein G) by replacing it with polyalanine, polythreonine, and diglycine segments at regions of the sequence that in the folded structure are alpha-helical, beta-strand, and turns, respectively. Remarkably, multiple folding and unfolding events are observed in a 15-micros molecular dynamics simulation at 330 K. The most stable state (populated at approximately 20%) of the simplified-sequence variant of protein G has the same alpha/beta topology as the wild-type but shows the characteristics of a molten globule, i.e., loose contacts among side chains and lack of a specific hydrophobic core. The unfolded state is heterogeneous and includes a variety of alpha/beta topologies but also fully alpha-helical and fully beta-sheet structures. Transitions within the denatured state are very fast, and the molten-globule state is reached in <1 micros by a framework mechanism of folding with multiple pathways. The native structure of the wild-type is more rigid than the molten-globule conformation of the simplified-sequence variant. The difference in structural stability and the very fast folding of the simplified protein suggest that evolution has enriched the primordial alphabet of amino acids mainly to optimize protein function by stabilization of a unique structure with specific tertiary interactions.
منابع مشابه
Overcoming the Crudeness of Energy Estimates in Protein 3D Structure Prediction by Homologs: The When and the How
One still cannot predict the 3D fold of a protein from its amino acid sequence alone, mainly because of errors in the energy estimates underlying the prediction. However, a recently developed theory [Finkelstein, A.V., Phys. Rev. Lett., 1998, vol. 80, pp. 4823–4825] shows that having a set of homologs (i.e., chains with equal 3D folds in spite of numerous mutations) one can average the potentia...
متن کاملDoes a cell protein explain Covid-19 severity
Does a protein on the surface of some of our cells explain why certain people are more at risk from covid-19? The coronavirus attaches to a receptor protein on the surface(ACE) of our cells to gain entry to them. The protein is carried by cells in the nose, lungs and gut. It is possible that variation in how much of this protein people have may help explain why some are more likely to die from ...
متن کاملFunnel-like organization in sequence space determines the distributions of protein stability and folding rate preferred by evolution.
To understand the physical and evolutionary determinants of protein folding, we map out the complete organization of thermodynamic and kinetic properties for protein sequences that share the same fold. The exhaustive nature of our study necessitates using simplified models of protein folding. We obtain a stability map and a folding rate map in sequence space. Comparison of the two maps reveals ...
متن کاملOn Simplified Global Nonlinear Function for Fitness Landscape: A Case Study of Inverse Protein Folding
The construction of fitness landscape has broad implication in understanding molecular evolution, cellular epigenetic state, and protein structures. We studied the problem of constructing fitness landscape of inverse protein folding or protein design, with the aim to generate amino acid sequences that would fold into an a priori determined structural fold which would enable engineering novel or...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Biophysical journal
دوره 97 6 شماره
صفحات -
تاریخ انتشار 2009