Capillarity-like growth of protein folding nuclei

We analyzed folding routes predicted by a variational model in terms of a generalized formalism of the capillarity scaling theory for 28 two-state proteins. The scaling exponent ranged from 0.2 to 0.45 with an average of 0.33. This average value corresponds to packing of rigid objects.That is, on average the folded core of the nucleus is found to be relatively diffuse. We also studied the growth of the folding nucleus and interface along the folding route in terms of the density or packing fraction. The evolution of the folded core and interface regions can be classified into three patterns of growth depending on how the growth of the folded core is balanced by changes in density of the interface. Finally, we quantified the diffuse versus polarized structure of the critical nucleus through direct calculation of the packing fraction of the folded core and interface regions. Our results support the general picture of describing protein folding as the capillarity-like growth of folding nuclei.Comment: 16 pages,6 figures. Submitted to Proc.Natl.Acad.Sc

Loop-closure principles in protein folding

Simple theoretical concepts and models have been helpful to understand the folding rates and routes of single-domain proteins. As reviewed in this article, a physical principle that appears to underly these models is loop closure.Comment: 27 pages, 5 figures; to appear in Archives of Biochemistry and Biophysic

More is different: 50 years of nuclear BCS

Many of the concepts which are at the basis of the development associated with a quantitative treatment of the variety of phenomena associated with the spontaneous breaking of gauge symmetry in nuclei have been instrumental in connection with novel studies of soft matter, namely of protein evolution and protein folding. Although the route to these subjects and associated development does not necessarily imply the nuclear physics connection, such a connection has proven qualitatively and quantitatively inspiring. In particular to model protein evolution in terms of the alignment of quasispins displaying twenty different projections, one for each of the twenty amino acids occurring in nature, and the associated symmetry breaking in information (sequence) space. Emergent properties of the corresponding phase transition are domain walls which stabilize local elementary structures (LES), few groups of 10-20 aminoacids which become structured already in the denatured state provide the molecular recognition directing protein folding. In fact, their docking is closely related to the transition state of the process. While the two-step, yes or no, folding process, does not provide direct information concerning LES, one can force LES from virtual to become real, observable final state entities. Getting again inspiration from the nuclear case (virtual processes contributing to pair correlations can be forced to become real with the help of a probe which itself changes particle number by two), one would expect that to make real virtual LES, that is segments of the protein which already at an early stage of the folding process flicker in and out of their native conformation, one needs a probe which itself displays a similar behaviour. Peptides displaying a sequence identical to LES are such probes.Comment: Contribution to the Volume 50 years of Nuclear BCS edited by World Scientifi

Nucleation phenomena in protein folding: The modulating role of protein sequence

For the vast majority of naturally occurring, small, single domain proteins folding is often described as a two-state process that lacks detectable intermediates. This observation has often been rationalized on the basis of a nucleation mechanism for protein folding whose basic premise is the idea that after completion of a specific set of contacts forming the so-called folding nucleus the native state is achieved promptly. Here we propose a methodology to identify folding nuclei in small lattice polymers and apply it to the study of protein molecules with chain length N=48. To investigate the extent to which protein topology is a robust determinant of the nucleation mechanism we compare the nucleation scenario of a native-centric model with that of a sequence specific model sharing the same native fold. To evaluate the impact of the sequence's finner details in the nucleation mechanism we consider the folding of two non- homologous sequences. We conclude that in a sequence-specific model the folding nucleus is, to some extent, formed by the most stable contacts in the protein and that the less stable linkages in the folding nucleus are solely determined by the fold's topology. We have also found that independently of protein sequence the folding nucleus performs the same `topological' function. This unifying feature of the nucleation mechanism results from the residues forming the folding nucleus being distributed along the protein chain in a similar and well-defined manner that is determined by the fold's topological features.Comment: 10 Figures. J. Physics: Condensed Matter (to appear