Building blocks of protein structures – Physics meets Biology (original) (raw)

Unified perspective on proteins: A physics approach

Physical Review E, 2004

We study a physical system which, while devoid of the complexity one usually associates with proteins, nevertheless displays a remarkable array of protein-like properties. The constructive hypothesis that this striking resemblance is not accidental leads not only to a unified framework for understanding protein folding, amyloid formation and protein interactions but also has implications for natural selection.

A geometrical framework for thinking about proteins

bioRxiv (Cold Spring Harbor Laboratory), 2023

We present a model, based on symmetry and geometry, for proteins. Using elementary ideas from mathematics and physics, we derive the geometries of discrete helices and sheets. We postulate a compatible solvent-mediated emergent pairwise attraction that assembles these building blocks, while respecting their individual symmetries. Instead of seeking to mimic the complexity of proteins, we look for a simple abstraction of reality that yet captures the essence of proteins. We employ analytic calculations and detailed Monte Carlo simulations to explore some consequences of our theory. The predictions of our approach are in accord with experimental data. Our framework provides a rationalization for understanding the common characteristics of proteins. Our results show that the free energy landscape of a globular protein is pre-sculpted at the backbone level, sequences and functionalities evolve in the fixed backdrop of the folds determined by geometry and symmetry, and that protein structures are unique in being simultaneously characterized by stability, diversity, and sensitivity.

On the role of physics and evolution in dictating protein structure and function

Israel journal of chemistry, 2014

How many of the structural and functional properties of proteins are inherent? Computer simulations provide a powerful tool to address this question. A series of studies on QS, quasi-spherical, compact polypeptides which lack any secondary structure; ART, artificial, proteins comprised of compact homopolypeptides with protein-like secondary structure; and PDB, native, single domain proteins shows that essentially all native global folds, pockets and protein-protein interfaces are in the ART library. This suggests that many protein properties are inherent and that evolution is involved in fine-tuning. The completeness of the space of ligand binding pockets and protein-protein interfaces suggests that promiscuous interactions are intrinsic to proteins and that the capacity to perform the biochemistry of life at low level does not require evolution. If so, this has profound consequences for the origin of life.

Protein folding and the organization of the protein topology universe

Trends in Biochemical Sciences, 2005

The mechanism by which proteins fold to their native states has been the focus of intense research in recent years. The rate-limiting event in the folding reaction is the formation of a conformation in a set known as the transition-state ensemble. The structural features present within such ensembles have now been analysed for a series of proteins using data from a combination of biochemical and biophysical experiments together with computer-simulation methods. These studies show that the topology of the transition state is determined by a set of interactions involving a small number of key residues and, in addition, that the topology of the transition state is closer to that of the native state than to that of any other fold in the protein universe. Here, we review the evidence for these conclusions and suggest a molecular mechanism that rationalizes these findings by presenting a view of protein folds that is based on the topological features of the polypeptide backbone, rather than the conventional view that depends on the arrangement of different types of secondary-structure elements. By linking the folding process to the organization of the protein structure universe, we propose an explanation for the overwhelming importance of topology in the transition states for protein folding.

The role of protein homochirality in shaping the energy landscape of folding

Protein Science, 2007

The homochirality, or isotacticity, of the natural amino acids facilitates the formation of regular secondary structures such as α-helices and β-sheets. However, many examples exist in nature where novel polypeptide topologies use both l- and d-amino acids. In this study, we explore how stereochemistry of the polypeptide backbone influences basic properties such as compactness and the size of fold space by simulating both lattice and all-atom polypeptide chains. We formulate a rectangular lattice chain model in both two and three dimensions, where monomers are chiral, having the effect of restricting local conformation. Syndiotactic chains with alternating chirality of adjacent monomers have a very large ensemble of accessible conformations characterized predominantly by extended structures. Isotactic chains on the other hand, have far fewer possible conformations and a significant fraction of these are compact. Syndiotactic chains are often unable to access maximally compact states available to their isotactic counterparts of the same length. Similar features are observed in all-atom models of isotactic versus syndiotactic polyalanine. Our results suggest that protein isotacticity has evolved to increase the enthalpy of chain collapse by facilitating compact helical states and to reduce the entropic cost of folding by restricting the size of the unfolded ensemble of competing states.

Geometry and physics of proteins

Proteins: Structure, Function, and Genetics, 2002

A conceptual framework for understanding the protein folding problem has remained elusive in spite of many significant advances. We show that geometrical constraints imposed by chain connectivity, compactness, and the avoidance of steric clashes can be encompassed in a natural way using a three-body potential and lead to a selection in structure space, independent of chemical details. Strikingly, secondary motifs such as hairpins, sheets, and helices, which are the building blocks of protein folds, emerge as the chosen structures for segments of the protein backbone based just on elementary geometrical considerations. Proteins 2002;47:315-322.

THEORY OF PROTEIN FOLDING: The Energy Landscape Perspective

Annual Review of Physical Chemistry, 1997

The energy landscape theory of protein folding is a statistical description of a protein's potential surface. It assumes that folding occurs through organizing an ensemble of structures rather than through only a few uniquely defined structural intermediates. It suggests that the most realistic model of a protein is a minimally frustrated heteropolymer with a rugged funnel-like landscape biased toward the native structure. This statistical description has been developed using tools from the statistical mechanics of disordered systems, polymers, and phase transitions of finite systems. We review here its analytical background and contrast the phenomena in homopolymers, random heteropolymers, and protein-like heteropolymers that are kinetically and thermodynamically capable of folding. The connection between these statistical concepts and the results of minimalist models used in computer simulations is discussed. The review concludes with a brief discussion of how the theory helps in the interpretation of results from fast folding experiments and in the practical task of protein structure prediction.

Complex Molecules that Fold like Proteins Can Emerge Spontaneously

Journal of the American Chemical Society, 2018

Folding can bestow macromolecules with various properties, as evident from nature's proteins. Until now complex folded molecules are the product either of evolution or of an elaborate process of design and synthesis. We now show that molecules that fold in a well-defined architecture of substantial complexity can emerge autonomously and selectively from a simple precursor. Specifically, we have identified a self-synthesizing macrocyclic foldamer with a complex and unprecedented secondary and tertiary structure that constructs itself highly selectively from 15 identical peptide-nucleobase subunits, using a dynamic combinatorial chemistry approach. Folding of the structure drives its synthesis in 95% yield from a mixture of interconverting molecules of different ring sizes in a one-step process. Single-crystal X-ray crystallography and NMR reveal a folding pattern based on an intricate network of noncovalent interactions involving residues spaced apart widely in the linear sequence. These results establish dynamic combinatorial chemistry as a powerful approach to developing synthetic molecules with folding motifs of a complexity that goes well beyond that accessible with current design approaches. The fact that such molecules can form autonomously implies that they may have played a role in the origin of life at earlier stages than previously thought possible.

Topological origin of the protein folding transition

Physical Review E

In this paper, a geometrical and thermodynamical analysis of the global properties of the potential energy landscape of a minimalistic model of a polypeptide is presented. The global geometry of the potential energy landscape is supposed to contain relevant information about the properties of a given sequence of amino acids, that is, to discriminate between a random heteropolymer and a protein. By considering the SH3 and PYP protein-sequences and their randomized versions it turns out that in addition to the standard signatures of the folding transition-discriminating between protein sequences of amino acids and random heteropolymer sequences-also peculiar geometric signatures of the equipotential hypersurfaces in configuration space can discriminate between proteins and random heteropolymers. Interestingly, these geometric signatures are the "shadows" of deeper topological changes that take place in correspondence with the protein folding transition. The protein folding transition takes place in systems with a small number of degrees of freedom (very far from the Avogadro number) and in the absence of a symmetry-breaking phenomenon. Nevertheless, seen from the deepest level of topology changes of equipotential submanifolds of phase space, the protein folding transition fully qualifies as a phase transition.

Cunning simplicity of protein folding landscapes

Protein Engineering, Design and Selection, 2001

Funnel-like landscapes are widely used to visualize protein folding. It might seem that any funnel-like energy landscape helps to avoid the 'Levinthal paradox', i.e. to avoid sampling the impossibly large number of conformations for a folding protein. This cunning suggestion, reinforced by beautiful drawings of the energy funnels, stimulated some simple models of protein folding; one of them [D.J. Bicout and A. Szabo (2000) Protein Sci., 9, 452-465] is especially straightforward and instructive. A thorough analysis of this strict funnel model (which does not consider a nucleation of phase separation in the course of folding) shows that it cannot provide a simultaneous explanation for both major features observed for protein folding: (i) folding within non-astronomical time, and (ii) coexistence of the native and the unfolded states during the folding process. On the contrary, the nucleation mechanism of protein folding can account for both these major features simultaneously. Keywords: coexistence of the native and the unfolded phases/ folding nucleus/protein folding/rate of folding/thermodynamic mid-transition/transition state/two-state kinetics