Physics of Biomolecular Recognition and Conformational Dynamics

2021 ◽  
Author(s):  
Wen-Ting Chu ◽  
Zhiqiang Yan ◽  
Xiakun Chu ◽  
Xiliang Zheng ◽  
Zuojia Liu ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Conformational Changes ◽  
Large Scale ◽  
Energy Landscape ◽  
Conformational Dynamics ◽  
Experimental Investigations ◽  
Biomolecular Recognition ◽  
Energy Landscape Theory ◽  
Landscape Theory ◽  
Underlying Mechanisms

Abstract Biomolecular recognition usually leads to the formation of binding complexes, often accompanied by large-scale conformational changes. This process is fundamental to biological functions at the molecular and cellular levels. Uncovering the physical mechanisms of biomolecular recognition and quantifying the key biomolecular interactions are vital to understand these functions. The recently developed energy landscape theory has been successful in quantifying recognition processes and revealing the underlying mechanisms. Recent studies have shown that in addition to affinity, specificity is also crucial for biomolecular recognition. The proposed physical concept of intrinsic specificity based on the underlying energy landscape theory provides a practical way to quantify the specificity. Optimization of affinity and specificity can be adopted as a principle to guide the evolution and design of molecular recognition. This approach can also be used in practice for drug discovery using multidimensional screening to identify lead compounds. The energy landscape topography of molecular recognition is important for revealing the underlying flexible binding or binding-folding mechanisms. In this review, we first introduce the energy landscape theory for molecular recognition and then address four critical issues related to biomolecular recognition and conformational dynamics: (1) specificity quantification of molecular recognition; (2) evolution and design in molecular recognition; (3) flexible molecular recognition; (4) chromosome structural dynamics. The results described here and the discussions of the insights gained from the energy landscape topography can provide valuable guidance for further computational and experimental investigations of biomolecular recognition and conformational dynamics.

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.

scholarly journals Learning To Fold Proteins Using Energy Landscape Theory

2014 ◽  
Vol 54 (8-9) ◽  
pp. 1311-1337 ◽  
Author(s):  
Nicholas P. Schafer ◽  
Bobby L. Kim ◽  
Weihua Zheng ◽  
Peter G. Wolynes
Keyword(s):  
Energy Landscape ◽  
Energy Landscape Theory ◽  
Landscape Theory

scholarly journals Evolutionary differences in the ACE2 reveals the molecular origins of COVID-19 susceptibility

2021 ◽  
Author(s):  
Ryan R. Cheng ◽  
Esteban Dodero-Rojas ◽  
Michele Di Pierro ◽  
José Nelson Onuchic
Keyword(s):  
Protein Folding ◽  
Protein Sequence ◽  
Energy Landscape ◽  
Spike Protein ◽  
Receptor Protein ◽  
Energy Landscape Theory ◽  
Landscape Theory ◽  
Selection Of

We explore the energetic frustration patterns associated with the binding between the SARS-CoV-2 spike protein and the ACE2 receptor protein in a broad selection of animals. Using energy landscape theory and the concept of energy frustration—theoretical tools originally developed to study protein folding—we are able to identify interactions among residues of the spike protein and ACE2 that result in COVID-19 resistance. This allows us to identify whether or not a particular animal is susceptible to COVID-19 from the protein sequence of ACE2 alone. Our analysis predicts a number of experimental observations regarding COVID-19 susceptibility, demonstrating that this feature can be explained, at least partially, on the basis of theoretical means.

scholarly journals COVID-19: Energy landscape theory of SARS-CoV-2 complexes with Particulate Matter

2020 ◽  
Author(s):  
Gianluigi Zangari del Balzo
Keyword(s):  
Particulate Matter ◽  
Energy Landscape ◽  
The United States ◽  
Deep Penetration ◽  
Energy Landscape Theory ◽  
Landscape Theory ◽  
Italian Regions ◽  
Rapid Spread ◽  
Experimental Laboratory ◽  
Definition Of

In the past few days, the global scientific community has made much progress in research for the COVID-19 pandemic, but the new SARS-CoV-2 coronavirus has not yet been correctly characterized thermodynamically and much is still unknown. In particular, the current SARS-CoV-2 models lack the characterization of the virus system within its environment. This is a serious systematic error, which stands in the way of impeding research into the pandemic.In the present work, therefore, we consider the SARS-CoV-2 system with its environment, and we give a correct thermodynamic definition, through analysis and simulations, from air transport to cellular entry through the mechanism of receptor- mediated endocytosis.In studying the aerosol environment of the SARS-CoV-2 virus, we cannot omit the presence of nanoparticles or dust.Therefore, analyzing and comparing the air environments in China and Italy, we note that the Chinese and Italian regions which were at the beginning the most affected by the pandemic are also the most polluted. The same phenomenon is happening today for the United States and Brazil.We therefore propose an energy landscape theory of synergistic complexes of SARS- CoV-2 with particulate matter (PM).This could explain the optimized strategy of deep penetration of interstitial lung cells and the rapid spread of the pandemic in the most polluted areas of the planet. It could also explain the severity and difficulty of treating the forms of interstitial pneumonia occurred in Italy and worldwide.The energy landscape theory of complexes of SARS-CoV-2 with particulate matter (PM), leads to crucial methodological constraints aimed at containing systematic errors in experimental laboratory procedures and in mathematical modeling, which can allow and accelerate the definition of the mechanism of action of the virus and therefore the realization of the appropriate therapies and health protocols.

scholarly journals Identification of AtHsp90.6 involved in early embryogenesis and its structure prediction by molecular dynamics simulations

2019 ◽  
Vol 6 (5) ◽  
pp. 190219 ◽  
Author(s):  
An Luo ◽  
Xinbo Li ◽  
Xuecheng Zhang ◽  
Huadong Zhan ◽  
Hewei Du ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Molecular Chaperone ◽  
Structure Prediction ◽  
Protein Quality ◽  
Energy Landscape ◽  
Conformational Dynamics ◽  
Early Embryogenesis ◽  
Potential Analysis ◽  
Up States ◽  
Dynamics Simulations

Heat-shock protein of 90 kDa (Hsp90) is a key molecular chaperone involved in folding the synthesized protein and controlling protein quality. Conformational dynamics coupled to ATPase activity in N-terminal domain is essential for Hsp90's function. However, the relevant process is still largely unknown in plant Hsp90s, especially those required for plant embryogenesis which is inextricably tied up with human survival. Here, AtHsp90.6, a member of Hsp90 family in Arabidopsis , was firstly identified as a protein essential for embryogenesis. Thus we modelled AtHsp90.6 in its functionally closed ‘lid-down’ and open ‘lid-up’ states, exploring the nucleotide binding mechanism in these two states. Free energy landscape and electrostatic potential analysis revealed the switching mechanism between these two states. Collectively, this study quantitatively analysed the conformational changes of AtHsp90.6 bound to ATP or ADP. This result may help us understand the mechanism of action of AtHsp90.6 in future.

scholarly journals Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4

2018 ◽  
Author(s):  
D. R. Kattnig ◽  
C. Nielsen ◽  
I. A. Solov’yov
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Large Scale ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Quantum Processes ◽  
Helical Segment ◽  
High Betweenness ◽  
Dynamics Simulations ◽  
Fad Binding

AbstractBirds appear to be equipped with a light-dependent, radical-pair-based magnetic compass that relies on truly quantum processes. While the identity of the sensory protein has remained speculative, cryptochrome 4 has recently been identified as the most auspicious candidate. Here, we report on allatom molecular dynamics (MD) simulations addressing the structural reorganisations that accompany the photoreduction of the flavin cofactor in a model of the European robin cryptochrome 4 (ErCry4). Extensive MD simulations reveal that the photo-activation of ErCry4 induces large-scale conformational changes on short (hundreds of nanoseconds) timescales. Specifically, the photo-reduction is accompanied with the release of the C-terminal tail, structural rearrangements in the vicinity of the FAD-binding site, and the noteworthy formation of an α-helical segment at the N-terminal part. Some of these rearrangements appear to expose potential phosphorylation sites. We describe the conformational dynamics of the protein using a graph-based approach that is informed by the adjacency of residues and the correlation of their local motions. This approach reveals densely coupled reorganisation communities, which facilitate an efficient signal transduction due to a high density of hubs. These communities are interconnected by a small number of highly important residues characterized by high betweenness centrality. The network approach clearly identifies the sites restructuring upon photoactivation, which appear as protrusions or delicate bridges in the reorganisation network. We also find that, unlike in the homologous cryptochrome from D. melanogaster, the release of the C-terminal domain does not appear to be correlated with the transposition of a histidine residue close to the FAD cofactor.

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