scholarly journals Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A

2020 ◽  
Vol 11 (10) ◽  
pp. 2670-2680 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Arun A. Gupta ◽  
Gogulan Karunanithy ◽  
Antonia S. J. S. Mey ◽  
Charis Georgiou ◽  
...  
Keyword(s):  
Large Scale ◽  
Energy Landscape ◽  
Molecular Simulations ◽  
Cyclophilin A ◽  
Dynamic Design ◽  
Loop Motions

Molecular simulations were used to design large scale loop motions in the enzyme cyclophilin A and NMR and biophysical methods were employed to validate the models.

scholarly journals Dynamic design: manipulation of millisecond timescale motions on the energy landscape of Cyclophilin A

2018 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Arun A. Gupta ◽  
Gogulan Karunanithy ◽  
Antonia S. J. S. Mey ◽  
Charis Georgiou ◽  
...  
Keyword(s):  
Rational Design ◽  
Energy Landscape ◽  
Cyclophilin A ◽  
Design Strategy ◽  
Energy Landscapes ◽  
Conformational States ◽  
Dynamic Design ◽  
Markov State ◽  
Free Energy Landscapes ◽  
Tremendous Challenge

AbstractProteins need to interconvert between many conformations in order to function, many of which are formed transiently, and sparsely populated. Particularly when the lifetimes of these states approach the millisecond timescale, identifying the relevant structures and the mechanism by which they inter-convert remains a tremendous challenge. Here we introduce a novel combination of accelerated MD (aMD) simulations and Markov State modelling (MSM) to explore these ‘excited’ conformational states. Applying this to the highly dynamic protein CypA, a protein involved in immune response and associated with HIV infection, we identify five principally populated conformational states and the atomistic mechanism by which they interconvert. A rational design strategy predicted that the mutant D66A should stabilise the minor conformations and substantially alter the dynamics whereas the similar mutant H70A should leave the landscape broadly unchanged. These predictions are confirmed using CPMG and R1ρ solution state NMR measurements. By accurately and reliably exploring functionally relevant, but sparsely populated conformations with milli-second lifetimesin silico, our aMD/MSM method has tremendous promise for the design of dynamic protein free energy landscapes for both protein engineering and drug discovery.

scholarly journals Metastable Intermediates as Stepping Stones on the Maturation Pathways of Viral Capsids

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Giovanni Cardone ◽  
Robert L. Duda ◽  
Naiqian Cheng ◽  
Lili You ◽  
James F. Conway ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Large Scale ◽  
Structural Changes ◽  
Energy Landscape ◽  
Potential Hazard ◽  
Stepping Stones ◽  
Scanning Calorimetry ◽  
Conformational Effects ◽  
Capsid Maturation ◽  
Capsid Integrity

ABSTRACT As they mature, many capsids undergo massive conformational changes that transform their stability, reactivity, and capacity for DNA. In some cases, maturation proceeds via one or more intermediate states. These structures represent local minima in a rich energy landscape that combines contributions from subunit folding, association of subunits into capsomers, and intercapsomer interactions. We have used scanning calorimetry and cryo-electron microscopy to explore the range of capsid conformations accessible to bacteriophage HK97. To separate conformational effects from those associated with covalent cross-linking (a stabilization mechanism of HK97), a cross-link-incompetent mutant was used. The mature capsid Head I undergoes an endothermic phase transition at 60°C in which it shrinks by 7%, primarily through changes in its hexamer conformation. The transition is reversible, with a half-life of ~3 min; however, >50% of reverted capsids are severely distorted or ruptured. This observation implies that such damage is a potential hazard of large-scale structural changes such as those involved in maturation. Assuming that the risk is lower for smaller changes, this suggests a rationalization for the existence of metastable intermediates: that they serve as stepping stones that preserve capsid integrity as it switches between the radically different conformations of its precursor and mature states. IMPORTANCE Large-scale conformational changes are widespread in virus maturation and infection processes. These changes are accompanied by the release of conformational free energy as the virion (or fusogenic glycoprotein) switches from a precursor state to its mature state. Each state corresponds to a local minimum in an energy landscape. The conformational changes in capsid maturation are so radical that the question arises of how maturing capsids avoid being torn apart. Offering proof of principle, severe damage is inflicted when a bacteriophage HK97 capsid reverts from the (nonphysiological) state that it enters when heated past 60°C. We suggest that capsid proteins have been selected in part by the criterion of being able to avoid sustaining collateral damage as they mature. One way of achieving this—as with the HK97 capsid—involves breaking the overall transition down into several smaller steps in which the risk of damage is reduced.

A Predictive Energy Landscape Model of Metamorphic Protein Conformational Specificity

2021 ◽  
Author(s):  
James O. Wrabl ◽  
Keila Voortman-Sheetz ◽  
Vincent J. Hilser
Keyword(s):  
Amino Acid ◽  
Structure Prediction ◽  
Large Scale ◽  
Energy Landscape ◽  
Thermodynamic Approach ◽  
High Identity ◽  
Denatured State ◽  
Metamorphic Protein ◽  
The Stability ◽  
The Impact

'Metamorphic' proteins challenge state-of-the-art structure prediction methods reliant on amino acid similarity. Unfortunately, this obviates a more effective thermodynamic approach necessary to properly evaluate the impact of amino acid changes on the stability of two different folds. A vital capability of such a thermodynamic approach would be the quantification of the free energy differences between 1) the energy landscape minima of each native fold, and 2) each fold and the denatured state. Here we develop an energetic framework for conformational specificity, based on an ensemble description of protein thermodynamics. This energetic framework was able to successfully recapitulate the structures of high-identity engineered sequences experimentally shown to adopt either Streptococcus protein GA or GB folds, demonstrating that this approach indeed reflected the energetic determinants of fold. Residue-level decomposition of the conformational specificity suggested several testable hypotheses, notably among them that fold-switching could be affected by local de-stabilization of the populated fold at positions sensitive to equilibrium perturbation. Since this ensemble-based compatibility framework is applicable to any structure and any sequence, it may be practically useful for the future targeted design, or large-scale proteomic detection, of novel metamorphic proteins.

scholarly journals The Large Scale Energy Landscape of Randomly Pinned Objects

1996 ◽  
Vol 6 (8) ◽  
pp. 1007-1020 ◽  
Author(s):  
Leon Balents ◽  
Jean-Philippe Bouchaud ◽  
Marc Mézard
Keyword(s):  
Large Scale ◽  
Energy Landscape

scholarly journals Energy landscape of LeuT from molecular simulations

2015 ◽  
Vol 143 (24) ◽  
pp. 243134 ◽  
Author(s):  
Mert Gur ◽  
Elia Zomot ◽  
Mary Hongying Cheng ◽  
Ivet Bahar
Keyword(s):  
Energy Landscape ◽  
Molecular Simulations

scholarly journals Large-scale Molecular Simulations of Hypervelocity Impact of Materials

2013 ◽  
Vol 58 ◽  
pp. 167-176 ◽  
Author(s):  
Andres Jaramillo-Botero ◽  
Qi An ◽  
Patrick L. Theofanis ◽  
William A. Goddard
Keyword(s):  
Large Scale ◽  
Molecular Simulations ◽  
Hypervelocity Impact

Erratum: Large scale molecular simulations of nanotoxicity

2014 ◽  
Vol 6 (4) ◽  
pp. 344-344
Author(s):  
Camilo A. Jimenez-Cruz ◽  
Seung-gu Kang ◽  
Ruhong Zhou
Keyword(s):  
Large Scale ◽  
Molecular Simulations
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