Protein folding and the organization of the protein topology universe (original) (raw)
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Journal of Polymer Science Part B: Polymer Physics, 2006
We compare folding trajectories of chymotrypsin inhibitor (CI2) using a dynamic Monte Carlo scheme with Go-type potentials. The model considers the four backbone atoms of each residue and a sphere centered around C b the diameter of which is chosen according to the type of the side group. Bond lengths and bond angles are kept fixed. Folding trajectories are obtained by giving random increments to the u and w torsion angles with some bias toward the native state. Excluded volume effects are considered. Two sets of 20 trajectories are obtained, with different initial configurations. The first set is generated from random initial configurations. The initial configurations of the second set are generated according to knowledge-based neighbor dependent torsion probabilities derived from triplets in the Protein Data Bank. Compared to chains with randomly generated initial configurations, those generated with neighbor-dependent probabilities (i) fold faster, (ii) have better defined secondary structure elements, and (iii) have less number of non-native contacts during folding.
Journal of Molecular Biology, 2008
The B-domain of protein A (BdpA) is a small 3-helix bundle that has been the subject of considerable experimental and theoretical investigation. Nevertheless, a unified view of the structure of the transition state ensemble (TSE) is still lacking. To characterize the TSE of this surprisingly challenging protein, we apply a combination of ψ-analysis (which probes the role of specific side chain to side chain contacts) and kinetic H/D amide isotope effects (which measures of hydrogen bond content), building upon previous studies using mutational φ-analysis (which probes the energetic influence of side chain substitutions). The second helix (H2) is folded in the TSE, while helix formation appears just at the carboxy and amino termini of the first and third helices, respectively. The experimental data suggest a homogenous, yet plastic TS with a native-like topology. This study generalizes our earlier conclusion, based on two larger α/β proteins, that the TSEs of most small proteins achieve ~70% of their native state's relative contact order. This high percentage limits the degree of possible TS heterogeneity and requires a re-evaluation of the structural content of the TSE of other proteins, especially when they are characterized as small or polarized.
Native topology or specific interactions: what is more important for protein folding?
Journal of Molecular Biology, 2001
Fifty-®ve molecular dynamics runs of two three-stranded antiparallel b-sheet peptides were performed to investigate the relative importance of amino acid sequence and native topology. The two peptides consist of 20 residues each and have a sequence identity of 15 %. One peptide has Gly-Ser (GS) at both turns, while the other has D-Pro-Gly (D PG). The simulations successfully reproduce the NMR solution conformations, irrespective of the starting structure. The large number of folding events sampled along the trajectories at 360 K (total simulation time of about 5 ms) yield a projection of the free-energy landscape onto two signi®cant progress variables. The two peptides have compact denatured states, similar free-energy surfaces, and folding pathways that involve the formation of a b-hairpin followed by consolidation of the unstructured strand. For the GS peptide, there are 33 folding events that start by the formation of the 2-3 b-hairpin and 17 with ®rst the 1-2 b-hairpin. For the D PG peptide, the statistical predominance is opposite, 16 and 47 folding events start from the 2-3 b-hairpin and the 1-2 b-hairpin, respectively. These simulation results indicate that the overall shape of the free-energy surface is de®ned primarily by the native-state topology, in agreement with an ever-increasing amount of experimental and theoretical evidence, while the amino acid sequence determines the statistically predominant order of the events.
Equilibrium folding pathways for model proteins
Journal of Statistical Physics, 1983
Protein conformations have been generated with both a Monte Carlo scheme and a simpler two-state noninteracting globule-coil model. Conformational energies are taken to consist of intraresidue and interresidue terms. Interresidue energies are taken to be proportional to the number of nativelike contacts. To describe probable folding pathways, either energy or the number of native residues are employed as simple one-dimensional folding-unfolding coordinates. By considering only conformations at each point on these coordinates, it is possible to obtain detailed conformational descriptions of relatively rare intermediates on the folding pathway. This technique of "trapping" intermediates and statistically characterizing them is useful for studying conformational transitions. Equilibrium folding-unfolding pathways have been constructed by connecting most probable conformations in order along the folding coordinate. Calculations with the noninteracting globule-coil model have been performed with details chosen to correspond to those in the Monte Carlo calculation for pancreatic trypsin inhibitor. Both pathways are similar. The a helix appears prior to formation of the central beta sheet; beta sheet formation coincides with a large maximum in the free energy because of the attendant loss of conformational entropy. Subsequently the Monte Carlo method indicates two alternative pathways for growth toward either the amino or the carboxyl terminus, followed by completion of the native form. For the globule-coil model, the growth pattern differs somewhat, with the appearance of the single pathway for folding up to the carboxyl terminus prior to completion of folding. This difference may originate in the Monte Carlo sampling procedures or in the simplifications of the globule-coil model.
Morphogenesis of a protein: folding pathways and the energy landscape1
Biochemical Society …, 2012
Current knowledge on the reaction whereby a protein acquires its native three-dimensional structure was obtained by and large through characterization of the folding mechanism of simple systems. Given the multiplicity of amino acid sequences and unique folds, it is not so easy, however, to draw general rules by comparing folding pathways of different proteins. In fact, quantitative comparison may be jeopardized not only because of the vast repertoire of sequences but also in view of a multiplicity of structures of the native and denatured states. We have tackled the problem of the relationships between the sequence information and the folding pathway of a protein, using a combination of kinetics, protein engineering and computational methods, applied to relatively simple systems. Our strategy has been to investigate the folding mechanism determinants using two complementary approaches, i.e. (i) the study of members of the same family characterized by a common fold, but substantial differences in amino acid sequence, or (ii) heteromorphic pairs characterized by largely identical sequences but with different folds. We discuss some recent data on protein-folding mechanisms by presenting experiments on different members of the PDZ domain family and their circularly permuted variants. Characterization of the energetics and structures of intermediates and TSs (transition states), obtained by -value analysis and restrained MD (molecular dynamics) simulations, provides a glimpse of the malleability of the dynamic states and of the role of the topology of the native states and of the denatured states in dictating folding and misfolding pathways.
Common Motifs and Topological Effects in the Protein Folding Transition State
Journal of Molecular Biology, 2006
Through extensive experiment, simulation, and analysis of protein S6 (1RIS), we find that variations in nucleation and folding pathway between circular permutations are determined principally by the restraints of topology and specific nucleation, and affected by changes in chain entropy. Simulations also relate topological features to experimentally measured stabilities. Despite many sizable changes in f values and the structure of the transition state ensemble that result from permutation, we observe a common theme: the critical nucleus in each of the mutants share a subset of residues that can be mapped to the critical nucleus residues of the wild-type. Circular permutations create new N and C termini, which are the location of the largest disruption of the folding nucleus, leading to a decrease in both f values and the role in nucleation. Mutant nuclei are built around the wild-type nucleus but are biased towards different parts of the S6 structure depending on the topological and entropic changes induced by the location of the new N and C termini.
Protein folding: search for basic physical models
2003
How a unique three-dimensional structure is rapidly formed from the linear sequence of a polypeptide is one of the important questions in contemporary science. Apart from biological context of in vivo protein folding (which has been studied only for a few proteins), the roles of the fundamental physical forces in the in vitro folding remain largely unstudied. Despite a degree of success in using descriptions based on statistical and/or thermodynamic approaches, few of the current models explicitly include more basic physical forces (such as electrostatics and Van Der Waals forces). Moreover, the present-day models rarely take into account that the protein folding is, essentially, a rapid process that produces a highly specific architecture. This review considers several physical models that may provide more direct links between sequence and tertiary structure in terms of the physical forces. In particular, elaboration of such simple models is likely to produce extremely effective computational techniques with value for modern genomics.
Small Proteins Fold Through Transition States With Native-like Topologies
Journal of Molecular Biology, 2006
The folding pathway of common-type acyl phosphatase (ctAcP) is characterized using ψ-analysis, which identifies specific chain-chain contacts using bi-histidine (biHis) metal-ion binding sites. In the transition state ensemble (TSE), the majority of the protein is structured with a nearnative topology, only lacking one β-strand and an α-helix. ψ-Values are zero or unity for all sites except one at the amino terminus of helix H2. This fractional ψ-value remains unchanged when three metal ions of differing coordination geometries are used, indicating this end of the helix experiences microscopic heterogeneity through fraying in the TSE. Ubiquitin, the other globular protein characterized using ψ-analysis, also exhibits a single consensus TSE structure. Hence, the TSE of both proteins have converged to a single configuration, albeit one that contains some fraying at the periphery. Models of the TSE of both proteins are created using all-atom Langevin dynamics simulations using distance constraints derived from the experimental ψ-values. For both proteins, the relative contact order of the TS models is ∼80% of the native value. This shared value viewed in the context of the known correlation between contact order and folding rates, suggests that other proteins will have a similarly high fraction of the native contact order. This constraint greatly limits the range of possible configurations at the rate-limiting step.