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In the Multi-domain Protein Adenylate Kinase, Domain Insertion Facilitates Cooperative Folding while Accommodating Function at Domain Interfaces  [PDF]
V. V. Hemanth Giri Rao,Shachi Gosavi
PLOS Computational Biology , 2014, DOI: doi/10.1371/journal.pcbi.1003938
Abstract: Having multiple domains in proteins can lead to partial folding and increased aggregation. Folding cooperativity, the all or nothing folding of a protein, can reduce this aggregation propensity. In agreement with bulk experiments, a coarse-grained structure-based model of the three-domain protein, E. coli Adenylate kinase (AKE), folds cooperatively. Domain interfaces have previously been implicated in the cooperative folding of multi-domain proteins. To understand their role in AKE folding, we computationally create mutants with deleted inter-domain interfaces and simulate their folding. We find that inter-domain interfaces play a minor role in the folding cooperativity of AKE. On further analysis, we find that unlike other multi-domain proteins whose folding has been studied, the domains of AKE are not singly-linked. Two of its domains have two linkers to the third one, i.e., they are inserted into the third one. We use circular permutation to modify AKE chain-connectivity and convert inserted-domains into singly-linked domains. We find that domain insertion in AKE achieves the following: (1) It facilitates folding cooperativity even when domains have different stabilities. Insertion constrains the N- and C-termini of inserted domains and stabilizes their folded states. Therefore, domains that perform conformational transitions can be smaller with fewer stabilizing interactions. (2) Inter-domain interactions are not needed to promote folding cooperativity and can be tuned for function. In AKE, these interactions help promote conformational dynamics limited catalysis. Finally, using structural bioinformatics, we suggest that domain insertion may also facilitate the cooperative folding of other multi-domain proteins.
Folding of the Protein Domain hbSBD  [PDF]
Maksim Kouza,Chi-Fon Chang,Shura Hayryan,Tsan-hung Yu,Mai Suan Li,Tai-huang Huang,Chin-Kun Hu
Quantitative Biology , 2006, DOI: 10.1529/biophysj.105.065151
Abstract: The folding of the alpha-helice domain hbSBD of the mammalian mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex is studied by the circular dichroism technique in absence of urea. Thermal denaturation is used to evaluate various thermodynamic parameters defining the equilibrium unfolding, which is well described by the two-state model with the folding temperature T_f = 317.8 K and the enthalpy change Delta H_g = 19.67 kcal/mol. The folding is also studied numerically using the off-lattice coarse-grained Go model and the Langevin dynamics. The obtained results, including the population of the native basin, the free energy landscape as a function of the number of native contacts and the folding kinetics, also suggest that the hbSBD domain is a two-state folder. These results are consistent with the biological function of hbSBD in BCKD.
Simple Models of the Protein Folding Problem  [PDF]
Chao Tang
Quantitative Biology , 1999, DOI: 10.1016/S0378-4371(00)00413-1
Abstract: The protein folding problem has attracted an increasing attention from physicists. The problem has a flavor of statistical mechanics, but possesses the most common feature of most biological problems -- the profound effects of evolution. I will give an introduction to the problem, and then focus on some recent work concerning the so-called ``designability principle''. The designability of a structure is measured by the number of sequences that have that structure as their unique ground state. Structures differ drastically in terms of their designability; highly designable structures emerge with a number of associated sequences much larger than the average. These highly designable structures 1) possess ``proteinlike'' secondary structures and motifs, 2) are thermodynamically more stable, and 3) fold faster than other structures. These results suggest that protein structures are selected in nature because they are readily designed and stable against mutations, and that such selection simultaneously leads to thermodynamic stability and foldability. According to this picture, a key to the protein folding problem is to understand the emergence and the properties of the highly designable structures.
Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain  [PDF]
Greta Hultqvist, Avinash S. Punekar, Angela Morrone, Celestine N. Chi, ?ke Engstr?m, Maria Selmer, Stefano Gianni, Per Jemth
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050055
Abstract: Circular permutation is a common molecular mechanism for evolution of proteins. However, such re-arrangement of secondary structure connectivity may interfere with the folding mechanism causing accumulation of folding intermediates, which in turn can lead to misfolding. We solved the crystal structure and investigated the folding pathway of a circularly permuted variant of a PDZ domain, SAP97 PDZ2. Our data illustrate how well circular permutation may work as a mechanism for molecular evolution. The circular permutant retains the overall structure and function of the native protein domain. Further, unlike most examples in the literature, this circular permutant displays a folding mechanism that is virtually identical to that of the wild type. This observation contrasts with previous data on the circularly permuted PDZ2 domain from PTP-BL, for which the folding pathway was remarkably affected by the same mutation in sequence connectivity. The different effects of this circular permutation in two homologous proteins show the strong influence of sequence as compared to topology. Circular permutation, when peripheral to the major folding nucleus, may have little effect on folding pathways and could explain why, despite the dramatic change in primary structure, it is frequently tolerated by different protein folds.
Multi-Dimensional Theory of Protein Folding  [PDF]
Kazuhito Itoh,Masaki Sasai
Quantitative Biology , 2009, DOI: 10.1063/1.3097018
Abstract: Theory of multi-dimensional representation of free energy surface of protein folding is developed by adopting structural order parameters of multiple regions in protein as multiple coordinates. Various scenarios of folding are classified in terms of cooperativity within individual regions and interactions among multiple regions and thus obtained classification is used to analyze the folding process of several example proteins. Ribosomal protein S6, src-SH3 domain, CheY, barnase, and BBL domain are analyzed with the two-dimensional representation by using a structure-based Hamiltonian model. Extension to the higher dimensional representation leads to the finer description of the folding process. Barnase, NtrC, and an ankyrin repeat protein are examined with the three-dimensional representation. The multi-dimensional representation allows us to directly address questions on folding pathways, intermediates, and transition states.
The water factor in the protein-folding problem
Rocha, L.F.O.;Tarragó Pinto, M.E.;Caliri, A.;
Brazilian Journal of Physics , 2004, DOI: 10.1590/S0103-97332004000100013
Abstract: globular proteins are produced as a linear chain of aminoacids in water solution in the cell and, in the same aqueous environment, fold into their respective unique and functional native structures. in spite of this, many theoretical studies have tried to explain the folding process in vacuum, but in this paper we adopt an alternative point of view: the folding problem of heteropolymers is analyzed from the solvent perspective. the thermodynamics of the folding process is discussed for a non homogeneous system composed by the chain and solvent together; hydrophobic effects, modulated by the polar/nonpolar attributes of the residue sequence and by its corresponding steric specificities, are proposed as basic ingredients for the mechanisms of the folding process. these ideas are incorporated in both lattice and off-lattice models and treated by monte carlo simulations. configurational and thermodynamical results are compared with properties of real proteins. the results suggest that the folding problem of small globular protein can be considered as a process in which the mechanism to reach the native structure and the requirements for the globule stability are uncoupled.
The water factor in the protein-folding problem  [cached]
Rocha L.F.O.,Tarragó Pinto M.E.,Caliri A.
Brazilian Journal of Physics , 2004,
Abstract: Globular proteins are produced as a linear chain of aminoacids in water solution in the cell and, in the same aqueous environment, fold into their respective unique and functional native structures. In spite of this, many theoretical studies have tried to explain the folding process in vacuum, but in this paper we adopt an alternative point of view: the folding problem of heteropolymers is analyzed from the solvent perspective. The thermodynamics of the folding process is discussed for a non homogeneous system composed by the chain and solvent together; hydrophobic effects, modulated by the polar/nonpolar attributes of the residue sequence and by its corresponding steric specificities, are proposed as basic ingredients for the mechanisms of the folding process. These ideas are incorporated in both lattice and off-lattice models and treated by Monte Carlo simulations. Configurational and thermodynamical results are compared with properties of real proteins. The results suggest that the folding problem of small globular protein can be considered as a process in which the mechanism to reach the native structure and the requirements for the globule stability are uncoupled.
Towards Solving the Inverse Protein Folding Problem  [PDF]
Yoojin Hong,Kyung Dae Ko,Gaurav Bhardwaj,Zhenhai Zhang,Damian B. van Rossum,Randen L. Patterson
Computer Science , 2010,
Abstract: Accurately assigning folds for divergent protein sequences is a major obstacle to structural studies and underlies the inverse protein folding problem. Herein, we outline our theories for fold-recognition in the "twilight-zone" of sequence similarity (<25% identity). Our analyses demonstrate that structural sequence profiles built using Position-Specific Scoring Matrices (PSSMs) significantly outperform multiple popular homology-modeling algorithms for relating and predicting structures given only their amino acid sequences. Importantly, structural sequence profiles reconstitute SCOP fold classifications in control and test datasets. Results from our experiments suggest that structural sequence profiles can be used to rapidly annotate protein folds at proteomic scales. We propose that encoding the entire Protein DataBank (~1070 folds) into structural sequence profiles would extract interoperable information capable of improving most if not all methods of structural modeling.
Personification algorithm for protein folding problem: Improvements in PERM
Wenqi Huang,Zhipeng Lü
Chinese Science Bulletin , 2004, DOI: 10.1360/04we0083
Abstract: PERM is the most efficient approach for solving protein folding problem based on simple lattice model. In this article a personification explanation of PERM is proposed. A new version of PERM, population control algorithm with two main improvements is presented: one is that it is able to redefine the weight and its predicted value in PERM, and the other is that it is able to unify the calculation of weight when choosing possible branches. The improved PERM is more efficient than the previous version; specifically it can find the known lowest energy states for the four well-known difficult instances and is generally several to hundreds times faster than PERM. It is noteworthy that with the improved PERM we found new lowest energy configurations of three of the four difficult problems missed in previous papers.
The Role of Backbone Hydrogen Bonds in the Transition State for Protein Folding of a PDZ Domain  [PDF]
S?ren W. Pedersen, Greta Hultqvist, Kristian Str?mgaard, Per Jemth
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095619
Abstract: Backbone hydrogen bonds are important for the structure and stability of proteins. However, since conventional site-directed mutagenesis cannot be applied to perturb the backbone, the contribution of these hydrogen bonds in protein folding and stability has been assessed only for a very limited set of small proteins. We have here investigated effects of five amide-to-ester mutations in the backbone of a PDZ domain, a 90-residue globular protein domain, to probe the influence of hydrogen bonds in a β-sheet for folding and stability. The amide-to-ester mutation removes NH-mediated hydrogen bonds and destabilizes hydrogen bonds formed by the carbonyl oxygen. The overall stability of the PDZ domain generally decreased for all amide-to-ester mutants due to an increase in the unfolding rate constant. For this particular region of the PDZ domain, it is therefore clear that native hydrogen bonds are formed after crossing of the rate-limiting barrier for folding. Moreover, three of the five amide-to-ester mutants displayed an increase in the folding rate constant suggesting that the hydrogen bonds are involved in non-native interactions in the transition state for folding.
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