Determining protein loop conformation using scaling‐relaxation techniques

Zheng, Qiang; Rosenfeld, Rakefet; Vajda, Sándor; DeLisi, Charles

doi:10.1002/pro.5560020806

Cited by 63 publications

(38 citation statements)

References 23 publications

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“…Loop modeling in protein structures has been addressed using knowledge-based approaches (Blundell et al, 1988;Chothia et al, 1989), pattern matching of distance matrices (Jones & Thirup, 1986), ab initio approaches using conformational searching (Bruccoleri & Karplus, 1985, 1987Fine et al, 1986;Moult & James, 1986), simulated annealing (Collura et al, 1993), scaling-relaxation techniques (Zheng et al, 1993), and combinations of several of these (Martin et al, 1989). For our problem, we need to introduce a predetermined conformation into a native loop without perturbing the rest of the structure.…”

Section: Overview Of Methodsmentioning

confidence: 99%

Modeling studies of the change in conformation required for cleavage of limited proteolytic sites

1994

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Previous analyses of limited proteolytic sites within native, folded protein structures have shown that a significant conformational change is required in order to facilitate binding into the active site of the attacking proteinase. For the serine proteinases, the optimum conformation to match the proteinase binding-site geometry has been well characterized crystallographically by the conserved main-chain geometry of the reactive site loops of their protein inhibitors. A good substrate must adopt a conformation very similar to this "target" main-chain conformation prior to cleavage. Using a "loop-closure" modeling approach, we have tested the ability of a set of trypticlimited proteolytic sites to achieve this target conformation and further tested their suitability for cleavage. The results show that in most cases, significant changes in the conformation of at least 12 residues are required. All the putative tryptic cleavage sites in 1 protein, elastase, were also modeled and tested to compare the results to the actual nicksite in that protein. These results strongly suggest that large local motions proximate to the scissile bond are required for proteolysis, and it is this ability to unfold locally without perturbing the overall protein conformation that is the prime determinant for limited proteolysis.

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Section: Overview Of Methodsmentioning

confidence: 99%

Modeling studies of the change in conformation required for cleavage of limited proteolytic sites

1994

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“…The bond-scaling-relaxation algorithm is used in all calculations (Zheng et al, 1993a(Zheng et al, , 1993b. Briefly, a random conformation is generated and subsequently scaled to meet the end-to-end distance constraint.…”

Section: Methodsmentioning

confidence: 99%

“…In this paper we present a strategy for closing two proximate loops -each in the above size range -simultaneously and demonstrate that simultaneous closing of the loops consistently results in more accurate predictions than sequential closing. We use the bond-scaling-relaxation algorithm (Zheng et al, 1993a(Zheng et al, , 1993b, which has previously been shown to give satisfactory results when modeling single loops in a wide range of proteins. Previous work using this algorithm has determined that 100 initial random conformations generally suffice to find loop conformations close to the native structures for loops of seven residues.…”

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confidence: 99%

Simultaneous modeling of multiple loops in proteins

Rosenbach

Rosenfeld

1995

Protein Science

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The most reliable methods for predicting protein structure are by way of homologous extension, using structural information from a closely related protein, or by "threading" through a set of predefined protein folds ("inverse folding"). Both sets of methods provide a model for the core of the protein-the structurally conserved secondary structures. Due to the large variability both in sequence and size of the loops that connect these secondary structures, they generally cannot be modeled using these techniques. Loop-closure algorithms are aimed at predicting loop structures, given their end-to-end distance. Various such algorithms have been described, and all have been tested by predicting the structure of a single loop in a known protein. In this paper we propose a method, which is based on the bond-scaling-relaxation loop-closure algorithm, for simultaneously predicting the structures of multiple loops, and demonstrate that, for two spatially close loops, simultaneous closure invariably leads to more accurate predictions than sequential closure. The accuracy of the predictions obtained for pairs of loops in the size range of 5-7 residues each is comparable to that obtained by other methods, when predicting the structures of single loops: the RMS deviations from the native conformations of various test cases modeled are approximately 0.6-1.7 A for backbone atoms and 1.1-3.3 A for all-atoms.

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“…For instance, in the context of energyguided approaches, close-and-relax [66] or Molecular Dynamics methods [7,61] rely on atombased representation, but Monte Carlo methods [54] use either atom-based [8] or dihedral angle representations [10,37]. The later is used, for instance, in the concerted motion approaches where the Jacobian of the geometric conditions plays a central role in the transformation necessary to evaluate the Metropolis acceptance criterion [18].…”

Section: Related Workmentioning

confidence: 99%

Exploring the energy landscapes of flexible molecular loops using higher‐dimensional continuation

Porta

Jaillet

2012

J Comput Chem

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The conformational space of a flexible molecular loop includes the set of conformations fulfilling the geometric loop-closure constraints and its energy landscape can be seen as a scalar field defined on this implicit set. Higher-dimensional continuation tools, recently developed in Dynamical Systems and also applied to Robotics, provide efficient algorithms to trace out implicitly defined sets. This paper describes these tools and applies them to obtain full descriptions of the energy landscapes of short molecular loops that, otherwise, can only be partially explored, mainly via sampling. Moreover, to deal with larger loops, this paper exploits the higher-dimensional continuation tools to find local minima and minimum energy transition paths between them, without deviating from the loop-closure constraints. The proposed techniques are applied to previously studied molecules revealing the intricate structure of their energy landscapes. This paper introduces the use of higher-dimensional continuation tools to explore the energy landscapes of the implicitly-defined conformational spaces of flexible molecular loops. These tools produce an atlas composed by coordinated charts that parametrize the conformational space. The atlas captures the structure of this space, which determines the motion of the loop and the transition paths between conformations, something that is hard to obtain using existing approaches.

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Determining protein loop conformation using scaling‐relaxation techniques

Cited by 63 publications

References 23 publications

Modeling studies of the change in conformation required for cleavage of limited proteolytic sites

Modeling studies of the change in conformation required for cleavage of limited proteolytic sites

Simultaneous modeling of multiple loops in proteins

Exploring the energy landscapes of flexible molecular loops using higher‐dimensional continuation

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