Landscape-Based Protein Stability Analysis and Network Modeling of Multiple Conformational States of the SARS-CoV-2 Spike D614G Mutant: Conformational Plasticity and Frustration-Induced Allostery as Energetic Drivers of Highly Transmissible Spike Variants

Verkhivker, Gennady M.; Agajanian, Steve; Kassab, Ryan; Krishnan, Keerthi

doi:10.1021/acs.jcim.2c00124

Cited by 7 publications

(3 citation statements)

References 159 publications

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“…These results suggest that structural rigidity is compromised in NUDT15 due to variants that might affect the protein-drug interaction. These destabilizing mutations greatly affect the stability and integrity of the structure that influences the protein function by altering the protein flexibility and binding efficiency [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients

Janakiraman

Sudhan

Alsharif

et al. 2023

Journal of Genetic Engineering and Biotechnology

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Background Human nucleotide triphosphate diphosphatase (NUDT15) is one of the essential proteins involved in the hydrolysis of anti-cancer drugs against leukemia. Polymorphisms in NUDT15 significantly affect the hydrolysis activity that leads to side effects, including leucopenia. Drugs having a better affinity with NUDT15 protein and contributing stable conformation may benefit patients from leucopenia. Most frequent NUDT15 polymorphisms causing structure variability and their association with leukemia were screened. The selected protein variants and anti-cancer drug structures were collected. Further, molecular docking was performed between drugs and NUDT15 variants along with the wild-type. Finally, molecular dynamics were executed for 100 ns to understand the stability of the protein with the anti-cancer drug based on molecular trajectories. Results Three-dimensional structures of NUDT15 wild, the most frequent variants (Val18Ile, Arg139Cys, and Arg139), and the anti-cancer drugs (azathioprine, mercaptopurine, and thioguanine) were selected and retrieved from structure databases. On molecular docking the binding energies of anti-cancer drugs against NUDT15 structures ranged from − 5.0 to − 5.9 kcal/mol. Among them, azathioprine showed the highest affinities (− 7.3 kcal/mol) for the wild and variant structures. Additionally, the molecular dynamics suggest all analyzed NUDT15 were stable with azathioprine based on the dynamic trajectories. Conclusion Our results suggest azathioprine could be the preferable anti-cancer drug for the population with NUDT15 variants that could effectively be hydrolyzed as evidenced by molecular docking and dynamic simulation.

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Section: Discussionmentioning

confidence: 99%

Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients

Janakiraman

Sudhan

Alsharif

et al. 2023

Journal of Genetic Engineering and Biotechnology

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“…Such tasks particularly highlight the problem of computational cost and conformational sampling in MD simulations [ 125 ]. One of the possible ways to relieve computational costs is to transition from all-atom to coarse-grained models of proteins [ 102 , 114 , 126 ]. Other options are the use of accelerated molecular dynamics methods [ 84 , 127 ] and enhanced sampling techniques [ 84 , 128 , 129 , 130 , 131 ], including machine learning approaches [ 132 , 133 , 134 ].…”

Section: Determination Of Protein Stabilitymentioning

confidence: 99%

Conformational Stability and Denaturation Processes of Proteins Investigated by Electrophoresis under Extreme Conditions

Masson

Lushchekina

2022

Molecules

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The functional structure of proteins results from marginally stable folded conformations. Reversible unfolding, irreversible denaturation, and deterioration can be caused by chemical and physical agents due to changes in the physicochemical conditions of pH, ionic strength, temperature, pressure, and electric field or due to the presence of a cosolvent that perturbs the delicate balance between stabilizing and destabilizing interactions and eventually induces chemical modifications. For most proteins, denaturation is a complex process involving transient intermediates in several reversible and eventually irreversible steps. Knowledge of protein stability and denaturation processes is mandatory for the development of enzymes as industrial catalysts, biopharmaceuticals, analytical and medical bioreagents, and safe industrial food. Electrophoresis techniques operating under extreme conditions are convenient tools for analyzing unfolding transitions, trapping transient intermediates, and gaining insight into the mechanisms of denaturation processes. Moreover, quantitative analysis of electrophoretic mobility transition curves allows the estimation of the conformational stability of proteins. These approaches include polyacrylamide gel electrophoresis and capillary zone electrophoresis under cold, heat, and hydrostatic pressure and in the presence of non-ionic denaturing agents or stabilizers such as polyols and heavy water. Lastly, after exposure to extremes of physical conditions, electrophoresis under standard conditions provides information on irreversible processes, slow conformational drifts, and slow renaturation processes. The impressive developments of enzyme technology with multiple applications in fine chemistry, biopharmaceutics, and nanomedicine prompted us to revisit the potentialities of these electrophoretic approaches. This feature review is illustrated with published and unpublished results obtained by the authors on cholinesterases and paraoxonase, two physiologically and toxicologically important enzymes.

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“…MD simulations characterized the conformational landscapes of the full-length S protein trimers detailing conformational transitions between functional states and unveiling previously unknown cryptic pockets [ 65 ]. Our studies revealed that the SARS-CoV-2 S protein can function as an allosteric regulatory machinery that can exploit the intrinsic plasticity of functional regions controlled by stable allosteric hotspots to modulate specific regulatory and binding functions [ 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. A number of computational studies employed atomistic simulations and binding energy analysis to examine the interactions between the S-RBD Omicron and the ACE2 receptor.…”

Section: Introductionmentioning

confidence: 99%

Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms

et al. 2022

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In this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, and perturbation-based network profiling of allosteric interactions in the SARS-Cov-2 spike complexes with a panel of cross-reactive and ultra-potent single antibodies (B1-182.1 and A23-58.1) as well as antibody combinations (A19-61.1/B1-182.1 and A19-46.1/B1-182.1). Using this approach, we quantify the local and global effects of mutations in the complexes, identify protein stability centers, characterize binding energy hotspots, and predict the allosteric control points of long-range interactions and communications. Conformational dynamics and distance fluctuation analysis revealed the antibody-specific signatures of protein stability and flexibility of the spike complexes that can affect the pattern of mutational escape. A network-based perturbation approach for mutational profiling of allosteric residue potentials revealed how antibody binding can modulate allosteric interactions and identified allosteric control points that can form vulnerable sites for mutational escape. The results show that the protein stability and binding energetics of the SARS-CoV-2 spike complexes with the panel of ultrapotent antibodies are tolerant to the effect of Omicron mutations, which may be related to their neutralization efficiency. By employing an integrated analysis of conformational dynamics, binding energetics, and allosteric interactions, we found that the antibodies that neutralize the Omicron spike variant mediate the dominant binding energy hotpots in the conserved stability centers and allosteric control points in which mutations may be restricted by the requirements of the protein folding stability and binding to the host receptor. This study suggested a mechanism in which the patterns of escape mutants for the ultrapotent antibodies may not be solely determined by the binding interaction changes but are associated with the balance and tradeoffs of multiple local and global factors, including protein stability, binding affinity, and long-range interactions.

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Landscape-Based Protein Stability Analysis and Network Modeling of Multiple Conformational States of the SARS-CoV-2 Spike D614G Mutant: Conformational Plasticity and Frustration-Induced Allostery as Energetic Drivers of Highly Transmissible Spike Variants

Cited by 7 publications

References 159 publications

Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients

Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients

Conformational Stability and Denaturation Processes of Proteins Investigated by Electrophoresis under Extreme Conditions

Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms

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