Principles of protein folding — A perspective from simple exact models

Abstract

General principles of protein structure, stability, and folding kinetics have recently been explored in computer simulations of simple exact lattice models. These models represent protein chains at a rudimentary level, but they involve few parameters, approximations, or implicit biases, and they allow complete explorations of conformational and sequence spaces. Such simulations have resulted in testable predictions that are sometimes unanticipated: The folding code is mainly binary and delocalized throughout the amino acid sequence. The secondary and tertiary structures of a protein are specified mainly by the sequence of polar and nonpolar monomers. More specific interactions may refine the structure, rather than dominate the folding code. Simple exact models can account for the properties that characterize protein folding: two-state cooperativity, secondary and tertiary structures, and multistage folding kinetics-fast hydrophobic collapse followed by slower annealing. These studies suggest the possibility of creating "foldable" chain molecules other than proteins. The encoding of a unique compact chain conformation may not require amino acids; it may require only the ability to synthesize specific monomer sequences in which at least one monomer type is solvent-averse.Keywords: chain collapse; hydrophobic interactions; lattice models; protein conformations; protein folding; protein stabilityWe review the principles of protein structure, stability, and folding kinetics from the perspective of simple exact models. We focus on the "folding code''-how the tertiary structure and folding pathway of a protein are encoded in its amino acid sequence. Although native proteins are specific, compact, and often remarkably symmetrical structures, ordinary synthetic polymers in solution, glasses, or melts adopt large ensembles of more expanded conformations, with little intrachain organization. With simple exact models, we ask what are the fundamental causes of the differences between proteins and other polymers-What makes proteins special?One view of protein folding assumes that the "local" interactions among the near neighbors in the amino acid sequence, the interactions that form helices and turns, are the main determinants of protein structure. This assumption implies that isolated helices form early in the protein folding pathway and then assemble into the native tertiary structure (see Fig. 1). It is the premise behind the paradigm, primary + secondary -+ tertiary structure, that seeks computer algorithms to predict secondary structures from the sequence, and then to assemble them into the tertiary native structure.Here we review a simple model of an alternative view, its basis in experimental results, and its implications. We show how the nonlocal interactions that drive collapse processes in heteropolymers can give rise to protein structure, stability, and folding kinetics. This perspective is based on evidence that the folding code is not predominantly localized in short windows of the amino acid sequence. It...

Firefly luciferase mutants as sensors of proteome stress

“…From a thermodynamic perspective, the sequestration of the hydrophobic side chains from the solvent facilitates the formation of folding intermediates and therefore hydrophobic collapse occurs spontaneously and results in the formation of the molten globule state (Dill et al, 1995;Kauzmann, 1959). The second view about protein folding, also regarded as "framework model" postulates that the folding process is a directed process where the local interactions lead to the transient formation of the secondary structural elements.…”

“…There is a gradual build-up/layering of new structures over the previous ones which help in stabilization of folding intermediates. During this process, the water molecules are excluded from the hydrophobic core which minimizes the free energy and leads to the collapse of the partially folded polypeptide chain to its native state (Daggett and Fersht, 2003;Dill et al, 1995).…”

β‐strand interactions at the domain interface critical for the stability of human lens γD‐crystallin

“…[30][31][32][33][34] In a separate example, even the use of high resolution experimental techniques such as coupling of H/D exchange with 2D NMR only allows detection of intermediate states with almost native-like five-strand b-sheet conformation during the earliest stage of Ubiquitin folding. 35,36 Computer simulations of protein models at different resolutions, from simple lattice models (and off-lattice) [37][38][39] to continuum solvent models 38,40,41 to all-atom explicit solvent models, 42,43 have been used to supplement existing experimental techniques in understanding aspects of protein folding. 44,45 In principle, molecular dynamics (MD) simulations with an atomistic description of the protein and solvent molecules should provide the most realistic description of the protein folding landscapes.…”

Relative stability of de novo four–helix bundle proteins: Insights from coarse grained molecular simulations

“…[1][2][3][4] This observation has lead to a strategy for the design of de novo proteins based on the choice of amino acid sequences whose pattern of polar and nonpolar amino acids insures that hydrophobic residues will be buried on folding into the target structure. [3][4][5][6][7][8][9][10][11][12] Other considerations, such as secondary structure propensity, geometric packing, shape complementarity, salt-bridge specificity, and negative design can also play a role in further narrowing (optimizing) the sequences considered in the design process.…”

“…To address questions (2) and (3) we designed a number of a sequence ''mutations'': (i) three different mutations for the F21 sequence, which show a partial role of additional polar residues in stabilizing the four-helix fold as well as the possibility to further optimize F21 by inserting nonpolar residues in ad hoc positions and (ii) one mutation for the F14 sequence, which leads to an equilibrium structure population dominated by stable four-helix bundles.…”