Protein folding stability and binding interactions through the lens of evolution: a dynamical perspective

Modi, Tushar; Campitelli, Paul; Kazan, I. Can; Ozkan, S. Banu

doi:10.1016/j.sbi.2020.11.007

Cited by 37 publications

(46 citation statements)

References 76 publications

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“…These residues might be important for protein dynamics. 51,52 Very low activity (Group C2) was displayed by 12 well-folded and stable mutants of second-shell residues. These residues are located in places that ensure the exact positioning of the residues involved in catalysis.…”

Section: Discussionmentioning

confidence: 99%

“…Subtle effects (Group C1) were observed for a group of third‐shell residues containing glycines, prolines, and alanines, found mostly in solvent‐exposed loops (Table 1). These residues might be important for protein dynamics 51,52 . Very low activity (Group C2) was displayed by 12 well‐folded and stable mutants of second‐shell residues.…”

Section: Discussionmentioning

confidence: 99%

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The roles of highly conserved, non‐catalytic residues in class A β‐lactamases

Chikunova

Ubbink

2022

Protein Science

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Evolution minimizes the number of highly conserved amino acid residues in proteins to ensure evolutionary robustness and adaptability. The roles of all highly conserved, non-catalytic residues, 11% of all residues, in class A β-lactamase were analyzed by studying the effect of 146 mutations on in cell and in vitro activity, folding, structure, and stability. Residues around the catalytic residues (second shell) contribute to fine-tuning of the active site structure. Mutations affect the structure over the entire active site and can result in stable but inactive protein. Conserved residues farther away (third shell) ensure a favorable balance of folding versus aggregation or stabilize the folded form over the unfolded state. Once folded, the mutant enzymes are stable and active and show only localized structural effects. These residues are found in clusters, stapling secondary structure elements. The results give an integral picture of the different roles of essential residues in enzymes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The roles of highly conserved, non‐catalytic residues in class A β‐lactamases

Chikunova

Ubbink

2022

Protein Science

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“…Other work with ENMs has also touched upon mutability, dynamics and evolution of the protein. Increasingly, protein-dynamics research is exploring the interplay between protein dynamics and evolution, with help of the ENM, which allows rapid assessment of protein dynamics and is able to relate it to evolution at the level of individual residues [16, 17]. The essential global-mode structure turns out, for example, to be much more highly conserved through evolution, than high-frequency structure [18].…”

Section: Introductionmentioning

confidence: 99%

Optimising Elastic Network Models for Protein Dynamics and Allostery: Spatial and Modal Cut-offs and Backbone Stiffness

Dubanevics

McLeish

2022

Preprint

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The family of coarse-grained models for protein dynamics known as Elastic Network Models (ENMs) require a careful choice of parameters to represent well experimental measurements or fully-atomistic simulations. The most basic ENM that represents each protein residue by a node at the position of its C-alpha atom, all connected by springs of equal stiffness, up to a cut-off in distance. Even at this level, a choice is required of the optimum cut-off distance and the upper limit of elastic normal modes taken in any sum for physical properties, such as dynamic correlation or allosteric effects on binding. Additionally, backbone-enhanced ENM (BENM) may improve the model by allocating a higher stiffness to springs that connect along with the protein backbone. This work reports on the effect of varying these three parameters (distance and mode cutoffs, backbone stiffness) on the dynamical structure of three proteins, Catabolite Activator Protein (CAP), Glutathione S-transferase (GST), and the SARS-CoV- 2 Main Protease (Mpro). Our main results are: (1) balancing B-factor and dispersion-relation predictions, a near-universal optimal value of 8.5 angstroms is advisable for ENMs; (2) inhomogeneity in elasticity brings the first mode containing spatial structure not well-resolved by the ENM typically within the first 20; (3) the BENM only affects modes in the upper third of the distribution, and, additionally to the ENM, is only able to model the dispersion curve better in this vicinity; (4) BENM does not typically affect fluctuation-allostery, which also requires careful treatment of the effector binding to the host protein to capture.

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“…In our previous studies, we have used our proteindynamics based metric, Dynamic Flexibility Index (DFI) [20] to analyze how changes in the conformational dynamics modulate the function during evolution of several different type of protein systems such as Green Fluorescent proteins (GFP) [17], β-lactamase [19,21] and Thioredoxin (Thrx) [16]. DFI is a position specific metric which uses linear response theory to analyse MD trajectories to quantify the relative flexibility of a residue position with respect to the rest of the protein.…”

Section: Introductionmentioning

confidence: 99%

“…Using DFI analysis, we have shown that proteins adapt to new environments or enhance their enzymatic activity through hinge shift mechanism such that the flexibility profile associated with their function is altered through point mutations. Particularly, rigidification of some sites are compensated by enhancements in flexibility of other distal rigid sites [15,18,21]. Furthermore, during evolution, rather than directly mutating the active site residues, distal mutations modulate the flexibility of the functional sites to accommodate novel non-cognate substrate degradation while conserving the 3-D fold [15,16,18,22].…”

Section: Introductionmentioning

confidence: 99%

Vibrational density of states capture the role of dynamic allostery in protein evolution

Modi,

Heyden,

Ozkan

2021

Preprint

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Previous studies of the flexibilities of ancestral proteins suggests that proteins evolve their function by altering their native state ensemble. Here we propose a more direct method of visualizing this by measuring the changes in the vibrational density of states (VDOS) of proteins as they evolve. Through analysis of VDOS profiles of ancestral and extant proteins we observe that β-lactamase and thioredoxins evolve by altering their density of states in the terahertz region. Particularly, the shift in VDOS profiles between ancestral and extant proteins suggests that nature utilize dynamic allostery for functional evolution. Moreover, we also show that VDOS profile of individual position can be used to describe the flexibility changes, particularly those without any amino acid substitution.

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Protein folding stability and binding interactions through the lens of evolution: a dynamical perspective

Cited by 37 publications

References 76 publications

The roles of highly conserved, non‐catalytic residues in class A β‐lactamases

The roles of highly conserved, non‐catalytic residues in class A β‐lactamases

Optimising Elastic Network Models for Protein Dynamics and Allostery: Spatial and Modal Cut-offs and Backbone Stiffness

Vibrational density of states capture the role of dynamic allostery in protein evolution

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