Common attributes of native-state structures of proteins, disordered proteins, and amyloid

Abstract

We show that a framework derived from the common character of globular proteins can be used to understand the design of protein sequences, the behavior of intrinsically unstructured proteins, and the formation of amyloid fibrils in a unified manner. Our studies provide compelling support for the idea that protein native-state structures, the structures adopted by intrinsically unstructured proteins on binding as well as those of amyloid aggregates, all reside in a physical state of matter in which the free energy landscape is sculpted not by the specific sequence of amino acids, but rather by considerations of geometry and symmetry. We elucidate the key role played by sequence design in selecting the structure of choice from the predetermined menu of putative native-state structures.amyloid formation ͉ presculpted free energy landscape ͉ protein design ͉ protein folding I t is well known that the sequence of amino acids comprising a protein encodes its native-state structure. The protein folding problem, the determination of the native-state structure given a sequence of amino acids, however, has remained unsolved, in part because of the sheer complexity of the problem: the huge number of degrees of freedom associated with the protein atoms and the surrounding water molecules as well as the history dependence implicit in an evolutionary process. It was recently proposed (1, 2) that considerations of symmetry and geometry determine the limited menu of folded conformations from which a protein can choose for its native-state structure (3). Protein structures belong to a novel phase of matter associated with the marginally compact phase of short tubes with a thickness specially self-tuned to be comparable with the range of attractive interactions promoting the compaction. This phase is a finite size effect and exists only for relatively short tubes. That it is poised near a phase transition provides a simple explanation for the flexibility of native-state structures. The marginally compact phase is stabilized by the interplay of the hydrophobic (H) effect and hydrogen-bond formation. The structures that one finds in it are modular in construction, being made up of two principal building blocks, helices and planar sheets; the degeneracy is greatly reduced so that the number of the resulting energy minima is relatively small.The principal theme of our work is to present a unification of several seemingly distinct aspects of proteins within the unified framework sketched above, which is derived from the common characteristics of all proteins. We will tackle three issues: (i) protein design (4-12); (ii) intrinsically unstructured proteins (IUPs), which interact with different molecular partners and adopt relatively rigid conformations in the presence of natural ligands (13-19); and (iii) the propensity of proteins to misfold and aggregate leading to the formation of amyloid fibrils, which are implicated in debilitating human diseases (20-30) such as Alzheimer's, light-chain amyloidosis, type II diabetes, and spongiform...

Sequence dependent aggregation of peptides and fibril formation

“…Such symmetry and geometry consideration leads to a presculpted free energy landscape 30 with marginally compact protein-like ground states and low energy minima 33,34 . Interestingly, the model also shows a strong tendency of multiple chains to form amyloid-like aggregates 32,35 , similar to that found in higher resolution models 24,36,37 . Extensive simulations have been carried out by Auer and coworkers [38][39][40][41] to study the fibril formation of 12-mer homo-peptides using the tube model with a slightly different constraint on self-avoidance, showing useful insights on the nucleation mechanism 38,39 of fibril formation and on the equilibrium conditions between the fibrillar aggregates and the peptide solution 40,41 .…”

“…Previous study of the tube model 35 has shown that hydrophobic-polar sequence can select protein's secondary and tertiary structures. In particular, the HPPH and HPPPH patterns have been identified as strong α-formers, whereas the HPH pattern is a β-former.…”

“…The consideration of HP sequences is a minimalist approach in terms of sequence specificity, however is well supported in protein folding 35,42 . Furthermore, the rather simplicity of amyloid fibril structures also indicates a possible simplification of the amino acid sequence in determining aggregation properties.…”

A Polypeptide “Building Block” for the β-Trefoil Fold Identified by “Top-Down Symmetric Deconstruction”

“…17,18 Exact primarystructure symmetry within repeated domains provides opportunities for domain mismatches producing misfolded forms with near-native Gibbs energy, and low sequence identities could have a crucial and general role in safeguarding proteins against misfolding and aggregation; 19 furthermore, primary-structure symmetry is one feature of amyloid-type aggregates. 20 Thus, while symmetric protein architecture offers attractive advantages for de novo design, there is a need for novel approaches to successfully identify foldable peptide building blocks from those that might otherwise misfold or aggregate.…”

Amyloidogenic Potential of Transthyretin Variants

“…The algorithm is based on an energy function for specific ␤-aggregation, which was derived from a large group of non-redundant high resolution x-ray structures of globular proteins (44). The assumption that information regarding the structure of amyloid fibrils can be deduced by studying the structures of globular proteins rests on the well established observation (45,46) that the aggregation mediated by nonnative ␤-pairings is a possible mode that polypeptide chains may adopt against insufficient folding stability. By assuming that the globular protein data base represents a system in thermodynamic equilibrium at a single temperature, which is supposed to be roughly constant for all proteins in the data bank, it then follows that the propensities p ab P(A) of finding a given residue pair ab in the ensemble, with a and b facing each other in neighboring parallel (P) or antiparallel (A) ␤-strands, are given by p ab P(A) ϭ exp(ϪE ab P(A) ), where ϪE ab P(A) are effective adimensional energies, and both a and b run over the 20 different amino acids (47).…”