Computational simulations assessment of mutations impact on streptokinase (SK) from a group G streptococci with enhanced activity – insights into the functional roles of structural dynamics flexibility of SK and stabilization of SK–μplasmin catalytic complex

One of the major virulence factors of SARS-CoV-2, NSP1, is a vital drug target due to its role in host immune evasion through multiple pathways. NSP1 protein is associated with inhibiting host mRNA translation by binding to the small subunit of ribosome through its C-terminal region. Previously, we have shown the structural dynamics of NSP1 C-terminal region (NSP1-CTR) in different physiological environments. So, it would be very interesting to investigate the druggable compounds that could bind with NSP1-CTR. Here, in this article, we have performed the different spectroscopic technique-based binding assays of an anticancer drug Mitoxantrone dihydrochloride (MTX) against the NSP1-CTR. We have also performed molecular docking followed by computational simulations with two different forcefields up to one microsecond. Overall, our results have suggested good binding between NSP1-CTR and MTX and may have implications in developing therapeutic strategies targeting NSP1 protein of SARS-CoV-2.

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Functional Tradeoffs Carry Phenotypes Across the Valley of the Shadow of Death

Integrative and Comparative Biology ◽

10.1093/icb/icaa092 ◽

2020 ◽

Vol 60 (5) ◽

pp. 1268-1282 ◽

Cited By ~ 1

Author(s):

P David Polly

Keyword(s):

Phylogenetic Tree ◽

Optimal Solution ◽

Poor Performance ◽

Disruptive Selection ◽

Phenotypic Evolution ◽

Computational Simulations ◽

Functional Roles ◽

Specific Performance ◽

Proportional Contribution ◽

Intermediate Performance

Synopsis Functional tradeoffs are often viewed as constraints on phenotypic evolution, but they can also facilitate evolution across the suboptimal valleys separating performance peaks. I explore this process by reviewing a previously published model of how disruptive selection from competing functional demands defines an intermediate performance optimum for morphological systems that cannot simultaneously be optimized for all of the functional roles they must play. Because of the inherent tradeoffs in such a system, its optimal morphology in any particular environmental context will usually be intermediate between the performance peaks of the competing functions. The proportional contribution of each functional demand can be estimated by maximum likelihood from empirically observed morphologies, including complex ones measured with multivariate geometric morphometrics, using this model. The resulting tradeoff weight can be mapped onto a phylogenetic tree to study how the performance optimum has shifted across a functional landscape circumscribed by the function-specific performance peaks. This model of tradeoff evolution is sharply different from one in which a multipeak Ornstein–Uhlenbeck (OU) model is applied to a set of morphologies and a phylogenetic tree to estimate how many separate performance optima exist. The multi-peak OU approach assumes that each branch is pushed toward one of two or more performance peaks that exist simultaneously and are separated by valleys of poor performance, whereas the model discussed here assumes that each branch tracks a single optimal performance peak that wanders through morphospace as the balance of functional demands shifts. That the movements of this net performance peak emerge from changing frequencies of selection events from opposing functional demands are illustrated using a series of computational simulations. These simulations show how functional tradeoffs can carry evolution across putative performance valleys: even though intermediate morphologies may not perform optimally for any one function, they may represent the optimal solution in any environment in which an organism experiences competing functional demands.

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Structural dynamics of the SARS-CoV-2 frameshift-stimulatory pseudoknot reveal topologically distinct conformers

10.1101/2020.12.28.424630 ◽

2020 ◽

Author(s):

Krishna Neupane ◽

Meng Zhao ◽

Aaron Lyons ◽

Sneha Munshi ◽

Sandaru M Ileperuma ◽

...

Keyword(s):

Drug Discovery ◽

Optical Tweezers ◽

Structural Dynamics ◽

Drug Target ◽

Conformational Heterogeneity ◽

Computational Simulations ◽

Mechanical Tension ◽

Stem Loop ◽

Ribosomal Frameshifting ◽

Rna Pseudoknot

The RNA pseudoknot that stimulates −1 programmed ribosomal frameshifting in SARS coronavirus-2 (SARS-CoV-2) is a possible drug target. To understand how this 3-stemmed pseudoknot responds to the mechanical tension applied by ribosomes during translation, which is thought to play a key role during frameshifting, we probed its structural dynamics under tension using optical tweezers. Unfolding curves revealed that the frameshift signal formed multiple different structures: at least two distinct pseudoknotted conformers with different unfolding forces and energy barriers, as well as alternative stem-loop structures. Refolding curves showed that stem 1 formed first in the pseudoknotted conformers, followed by stem 3 and then stem 2. By extending the handle holding the RNA to occlude the 5′ end of stem 1, the proportion of the different pseudoknot conformers could be altered systematically, consistent with structures observed in cryo-EM images and computational simulations that had distinct topologies: the 5′ end of the RNA threaded through the 3-helix junction to form a ring-knot, or unthreaded as in more standard H-type pseudoknots. These results resolve the folding mechanism of the frameshift signal in SARS-CoV-2 and highlight the dynamic conformational heterogeneity of this RNA, with important implications for structure-based drug-discovery efforts.

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Mapping Structural Dynamics of Proteins with Femtosecond Stimulated Raman Spectroscopy

Annual Review of Physical Chemistry ◽

10.1146/annurev-physchem-071119-040154 ◽

2020 ◽

Vol 71 (1) ◽

pp. 239-265 ◽

Cited By ~ 2

Author(s):

Chong Fang ◽

Longteng Tang

Keyword(s):

Biological Sciences ◽

Raman Spectroscopy ◽

Structural Dynamics ◽

Rational Design ◽

Theoretical Concepts ◽

Functional Roles ◽

Cellular Processes ◽

Frequency Domains ◽

Dynamic Resonance ◽

Stimulated Raman

The structure–function relationships of biomolecules have captured the interest and imagination of the scientific community and general public since the field of structural biology emerged to enable the molecular understanding of life processes. Proteins that play numerous functional roles in cellular processes have remained in the forefront of research, inspiring new characterization techniques. In this review, we present key theoretical concepts and recent experimental strategies using femtosecond stimulated Raman spectroscopy (FSRS) to map the structural dynamics of proteins, highlighting the flexible chromophores on ultrafast timescales. In particular, wavelength-tunable FSRS exploits dynamic resonance conditions to track transient-species-dependent vibrational motions, enabling rational design to alter functions. Various ways of capturing excited-state chromophore structural snapshots in the time and/or frequency domains are discussed. Continuous development of experimental methodologies, synergistic correlation with theoretical modeling, and the expansion to other nonequilibrium, photoswitchable, and controllable protein systems will greatly advance the chemical, physical, and biological sciences.

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Structural dynamics of P-type ATPase ion pumps

Biochemical Society Transactions ◽

10.1042/bst20190124 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1247-1257 ◽

Cited By ~ 17

Author(s):

Mateusz Dyla ◽

Sara Basse Hansen ◽

Poul Nissen ◽

Magnus Kjaergaard

Keyword(s):

Structural Dynamics ◽

Single Molecule ◽

New Technologies ◽

Atp Hydrolysis ◽

Resonance Energy Transfer ◽

Resonance Energy ◽

Time Resolved ◽

Dynamics Simulations ◽

Types Of Information ◽

P Type

Abstract P-type ATPases transport ions across biological membranes against concentration gradients and are essential for all cells. They use the energy from ATP hydrolysis to propel large intramolecular movements, which drive vectorial transport of ions. Tight coordination of the motions of the pump is required to couple the two spatially distant processes of ion binding and ATP hydrolysis. Here, we review our current understanding of the structural dynamics of P-type ATPases, focusing primarily on Ca2+ pumps. We integrate different types of information that report on structural dynamics, primarily time-resolved fluorescence experiments including single-molecule Förster resonance energy transfer and molecular dynamics simulations, and interpret them in the framework provided by the numerous crystal structures of sarco/endoplasmic reticulum Ca2+-ATPase. We discuss the challenges in characterizing the dynamics of membrane pumps, and the likely impact of new technologies on the field.

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