Sampling of the native conformational ensemble of myoglobin via structures in different crystalline environments

Kondrashov, D.A.; Zhang, Wei; Aranda, Roman; Stec, Boguslaw; Phillips, George N.

doi:10.1002/prot.21499

Cited by 49 publications

(59 citation statements)

References 55 publications

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“…An analysis of 43 T4 lysozyme molecules in 25 crystal lattices showed an average of 0.55 for the correlation coefficient of main chain B-factors, each against the average of all others (36), and B-factor distributions also vary significantly among four myoglobin structures (37). Calculated fluctuations are the same independent of crystal lattice, and we find that VAMM-NMA fluctuations correlate with the average B-factors from T4 lysozyme structures at the level of 0.66 and with the myoglobin averages at 0.75.…”

Section: Applications Energy Minimization With Truncated Newton Methodmentioning

confidence: 99%

“…A manageable set of 15 structures used for comparison of theoretical and experimental B-factors was chosen from a large set of high-resolution structures analyzed by Eyal et al (37), such as to have virtually the same average correlation coefficient against ENM normal mode fluctuations for these 15 (0.59) as for all 176 (a range of 0.54 -0.58 with varying ENM parameters).…”

Section: Nma Elastic Networkmentioning

confidence: 99%

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A force field for virtual atom molecular mechanics of proteins

Korkut¹,

Hendrickson

2009

Proc. Natl. Acad. Sci. U.S.A.

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Activities of many biological macromolecules involve large conformational transitions for which crystallography can specify atomic details of alternative end states, but the course of transitions is often beyond the reach of computations based on full-atomic potential functions. We have developed a coarse-grained force field for molecular mechanics calculations based on the virtual interactions of C␣ atoms in protein molecules. This force field is parameterized based on the statistical distribution of the energy terms extracted from crystallographic data, and it is formulated to capture features dependent on secondary structure and on residue-specific contact information. The resulting force field is applied to energy minimization and normal mode analysis of several proteins. We find robust convergence in minimizations to low energies and energy gradients with low degrees of structural distortion, and atomic fluctuations calculated from the normal mode analyses correlate well with the experimental B-factors obtained from high-resolution crystal structures. These findings suggest that the virtual atom force field is a suitable tool for various molecular mechanics applications on large macromolecular systems undergoing large conformational changes.energy minimization ͉ normal modes ͉ transition pathways A ccurate understanding of the dynamic properties of proteins has been a major challenge in biophysics (1, 2). With advances in macromolecular crystallography, structural information has been obtained on very large complexes such as ribosome particles (3), chaperone complexes (4), virus particles (5), and RNA polymerases (6) as well as on thousands of individual proteins. In addition, snapshots of protein structures in different states of activity demonstrate the existence of very large conformational changes (7,8). Computational analysis of the dynamics of such systems is extremely difficult, if not impossible, when using full-atomic computational approaches, due not only to computational limitations but also to the complexity of the resulting information. Thus, coarse-grained approaches have gained importance for addressing large systems and large conformational changes (9-11).Coarse graining reduces computational complexity by greatly decreasing degrees of freedom of a molecular system with appropriate assumptions to achieve simplification without compromise of essential features (12). For reducing complexity in proteins, C␣-only models have been the most popular, but other coarse-graining approaches have also been taken, such as the inclusion of side-chain centroids (SCs) (13). An important aspect of coarse-grained analysis is the use of an appropriate pseudoforce field to model the forces and constraints exerted on the molecular system.The use of simple harmonic potentials to model the C␣-to-C␣ interactions in proteins as flexible springs has been most popular (14). Such simple harmonic potentials are very effective in defining the near-native-state fluctuations of proteins calculated by elastic network models...

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Section: Applications Energy Minimization With Truncated Newton Methodmentioning

confidence: 99%

Section: Nma Elastic Networkmentioning

confidence: 99%

A force field for virtual atom molecular mechanics of proteins

Korkut¹,

Hendrickson

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Our underlying strategy is to treat molecular packing environments in crystal lattices derived from NCS and crystallization conditions as a unique probe of dynamic behaviors of proteins. As a consequence of such distinct environments, static and dynamic differences between crystal structures related by NCS are informative, independent measurements (6,19).…”

Section: Methodsmentioning

confidence: 99%

“…This paper harnesses structural evidence presently embedded in a large number of static and time-resolved structures of HbI and presents a simple cooperative mechanism. We take advantage of noncrystallographic symmetry (NCS) as a unique opportunity to examine asymmetric, but cooperative, behavior between subunits in different structural environments imposed by crystal lattices (6) (Fig. S1).…”

mentioning

confidence: 99%

Cooperative macromolecular device revealed by meta-analysis of static and time-resolved structures

Ren

Šrajer

Knapp

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Here we present a meta-analysis of a large collection of static structures of a protein in the Protein Data Bank in order to extract the progression of structural events during protein function. We apply this strategy to the homodimeric hemoglobin HbI from Scapharca inaequivalvis. We derive a simple dynamic model describing how binding of the first ligand in one of the two chemically identical subunits facilitates a second binding event in the other partner subunit. The results of our ultrafast time-resolved crystallographic studies support this model. We demonstrate that HbI functions like a homodimeric mechanical device, such as pliers or scissors. Ligandinduced motion originating in one subunit is transmitted to the other via conserved pivot points, where the E and F′ helices from two partner subunits are "bolted" together to form a stable dimer interface permitting slight relative rotation but preventing sliding.allostery | cooperativity | structural dynamics | time-resolved crystallography H emoglobins are molecular oxygen transporters in vertebrates and many invertebrates. Although the variety of quaternary assemblies of hemoglobins (1, 2) suggests considerable diversity in the strategies to achieve cooperativity, a general hypothesis remains valid: A newly ligated subunit communicates with its unligated partners via conformational changes, either tertiary or quaternary, thereby altering the ligand affinity of its partner subunits (3-5). However, the key question remains obscure: How are ligand-induced structural changes that originate in one subunit transmitted to the other to structurally modulate its ligand binding affinity? This paper harnesses structural evidence presently embedded in a large number of static and time-resolved structures of HbI and presents a simple cooperative mechanism. We take advantage of noncrystallographic symmetry (NCS) as a unique opportunity to examine asymmetric, but cooperative, behavior between subunits in different structural environments imposed by crystal lattices (6) (Fig. S1). The main finding of this study is summarized by an animated cartoon (Movie S1) showing our proposed cooperative mechanical model in action.Unlike mammalian hemoglobins, the interface of HbI homodimer consists of a longer and straight helix E and a bent helix F from each subunit (1, 7). These two helices hold a heme group in between (Figs. 1A and 2A). Each heme group is anchored to the proximal His101 located near the end of helix F. In this paper, we refer to the two subunits as A and B and the two helices in one subunit as E and F. The notations E′ and F′ refer to E and F in the partner subunit. ResultsHere we propose a simple mechanical model to explain the mechanism of cooperative change in ligand binding affinity in homodimeric HbI (Fig. 1A and Movies S1 and S2). In this model, motions transmit from one subunit to the other via two pairs of "bolted" helices E-F′ and E′-F at the dimer interface so that the majority of the intersubunit contacts remain undisturbed during transition between allo...

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“…Thus, structural sensitivity is an important quality parameter for protein property calculators 28 . For the present work, six different high-resolution crystal structures, 1A6G 44 , 1A6M 44 , 1BZ6 45 , 1BZP 45 , 1U7S46 , and 2EKT 47 , of sperm whale myoglobin were applied systematically to assess the accuracy of the six methods. Properties of these crystal structures are summarized inTable 1.…”

mentioning

confidence: 99%

Towards a “Golden Standard” for computing globin stability: Stability and structure sensitivity of myoglobin mutants

Kepp

2015

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Sampling of the native conformational ensemble of myoglobin via structures in different crystalline environments

Cited by 49 publications

References 55 publications

A force field for virtual atom molecular mechanics of proteins

A force field for virtual atom molecular mechanics of proteins

Cooperative macromolecular device revealed by meta-analysis of static and time-resolved structures

Towards a “Golden Standard” for computing globin stability: Stability and structure sensitivity of myoglobin mutants

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