R-3 Repository :: Browsing by Author "Noel, Jeffrey K."

Browsing by Author "Noel, Jeffrey K."

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Constructing a folding model for protein S6 guided by native fluctuations deduced from NMR structures
(AIP Publishing LLC., 2015) Lammert, Heiko; Noel, Jeffrey K.; Haglund, Ellinor; Schug, Alexander; Onuchic, José N.; Center for Theoretical Biological Physics
The diversity in a set of protein nuclear magnetic resonance (NMR) structures provides an estimate of native state fluctuations that can be used to refine and enrich structure-based protein models (SBMs). Dynamics are an essential part of a protein’s functional native state. The dynamics in the native state are controlled by the same funneled energy landscape that guides the entire folding process. SBMs apply the principle of minimal frustration, drawn from energy landscape theory, to construct a funneled folding landscape for a given protein using only information from the native structure. On an energy landscape smoothed by evolution towards minimal frustration, geometrical constraints, imposed by the native structure, control the folding mechanism and shape the native dynamics revealed by the model. Native-state fluctuations can alternatively be estimated directly from the diversity in the set of NMRstructures for a protein. Based on this information, we identify a highly flexible loop in the ribosomal protein S6 and modify the contact map in a SBM to accommodate the inferred dynamics. By taking into account the probable native state dynamics, the experimental transition state is recovered in the model, and the correct order of folding events is restored. Our study highlights how the shared energy landscape connects folding and function by showing that a better description of the native basin improves the prediction of the folding mechanism.
The Dominant Folding Route Minimizes Backbone Distortion in SH3
(2012-11-15) Lammert, Heiko; Noel, Jeffrey K.; Onuchic, José N.; Center for Theoretical Biological Physics
Generalized Manning Condensation Model Captures the RNA Ion Atmosphere
(American Physical Society, 2015) Hayes, Ryan L.; Noel, Jeffrey K.; Mandic, Ana; Whitford, Paul C.; Sanbonmatsu, Karissa Y.; Mohanty, Udayan; Onuchic, José N.; Center for Theoretical Biological Physics
RNA is highly sensitive to the ionic environment and typically requires Mg2+ to form compact structures. There is a need for models capable of describing the ion atmosphere surrounding RNA with quantitative accuracy. We present a model of RNA electrostatics and apply it within coarse-grained molecular dynamics simulation. The model treats Mg2+ ions explicitly to account for ion-ion correlations neglected by mean-field theories. Since mean-field theories capture KCl well, it is treated implicitly by a generalized Manning counterion condensation model. The model extends Manning condensation to deal with arbitrary RNA conformations, nonlimiting KCl concentrations, and the ion inaccessible volume of RNA. The model is tested against experimental measurements of the excess Mg2+ associated with the RNA, Γ2+, because Γ2+ is directly related to the Mg2+-RNA interaction free energy. The excellent agreement with experiment demonstrates that the model captures the ionic dependence of the RNA free energy landscape.
Geometrical Frustration in Interleukin-33 Decouples the Dynamics of the Functional Element from the Folding Transition State Ensemble
(Public Library of Science, 2015) Fisher, Kaitlin M.; Haglund, Ellinor; Noel, Jeffrey K.; Hailey, Kendra L.; Onuchic, José Nelson; Jennings, Patricia A.; Center for Theoretical Biological Physics
Interleukin-33 (IL-33) is currently the focus of multiple investigations into targeting pernicious inflammatory disorders. This mediator of inflammation plays a prevalent role in chronic disorders such as asthma, rheumatoid arthritis, and progressive heart disease. In order to better understand the possible link between the folding free energy landscape and functional regions in IL-33, a combined experimental and theoretical approach was applied. IL-33 is a pseudo- symmetrical protein composed of three distinct structural elements that complicate the folding mechanism due to competition for nucleation on the dominant folding route. Trefoil 1 constitutes the majority of the binding interface with the receptor whereas Trefoils 2 and 3 provide the stable scaffold to anchor Trefoil 1. We identified that IL-33 folds with a three-state mechanism, leading to a rollover in the refolding arm of its chevron plots in strongly native conditions. In addition, there is a second slower refolding phase that exhibits the same rollover suggesting similar limitations in folding along parallel routes. Characterization of the intermediate state and the rate limiting steps required for folding suggests that the rollover is attributable to a moving transition state, shifting from a post- to pre-intermediate transition state as you move from strongly native conditions to the midpoint of the transition. On a structural level, we found that initially, all independent Trefoil units fold equally well until a QCA of 0.35 when Trefoil 1 will backtrack in order to allow Trefoils 2 and 3 to fold in the intermediate state, creating a stable scaffold for Trefoil 1 to fold onto during the final folding transition. The formation of this intermediate state and subsequent moving transition state is a result of balancing the difficulty in folding the functionally important Trefoil 1 onto the remainder of the protein. Taken together our results indicate that the functional element of the protein is geometrically frustrated, requiring the more stable elements to fold first, acting as a scaffold for docking of the functional element to allow productive folding to the native state.
Lowered pH Leads to Fusion Peptide Release and a Highly Dynamic Intermediate of Influenza Hemagglutinin
(American Chemical Society, 2016) Lin, Xingcheng; Noel, Jeffrey K.; Wang, Qinghua; Ma, Jianpeng; Onuchic, José Nelson; Center for Theoretical Biological Physics
Hemagglutinin (HA), the membrane-bound fusion protein of the influenza virus, enables the entry of virus into host cells via a structural rearrangement. There is strong evidence that the primary trigger for this rearrangement is the low pH environment of a late endosome. To understand the structural basis and the dynamic consequences of the pH trigger, we employed explicit-solvent molecular dynamics simulations to investigate the initial stages of the HA transition. Our results indicate that lowered pH destabilizes HA and speeds up the dissociation of the fusion peptides (FPs). A buried salt bridge between the N-terminus and Asp1122 of HA stem domain locks the FPs and may act as one of the pH sensors. In line with recent observations from simplified protein models, we find that, after the dissociation of FPs, a structural order–disorder transition in a loop connecting the central coiled-coil to the C-terminal domains produces a highly mobile HA. This motion suggests the existence of a long-lived asymmetric or “symmetry-broken” intermediate during the HA conformational change. This intermediate conformation is consistent with models of hemifusion, and its early formation during the conformational change has implications for the aggregation seen in HA activity.
Magnesium Fluctuations Modulate RNA Dynamics in the SAM-I Riboswitch
(American Chemical Society, 2012) Hayes, Ryan L.; Noel, Jeffrey K.; Mohanty, Udayan; Whitford, Paul C.; Hennelly, Scott P.; Onuchic, José N.; Sanbonmatsu, Karissa Y.; Center for Theoretical Biological Physics
Experiments demonstrate that Mg2+ is crucial for structure and function of RNA systems, yet the detailed molecular mechanism of Mg2+ action on RNA is not well understood. We investigate the interplay between RNA and Mg2+ at atomic resolution through ten 2-μs explicit solvent molecular dynamics simulations of the SAM-I riboswitch with varying ion concentrations. The structure, including three stemloops, is very stable on this time scale. Simulations reveal that outer-sphere coordinated Mg2+ ions fluctuate on the same time scale as the RNA, and that their dynamics couple. Locally, Mg2+ association affects RNA conformation through tertiary bridging interactions; globally, increasing Mg2+ concentration slows RNA fluctuations. Outer-sphere Mg2+ ions responsible for these effects account for 80% of Mg2+ in our simulations. These ions are transiently bound to the RNA, maintaining interactions, but shuttled from site to site. Outer-sphere Mg2+ are separated from the RNA by a single hydration shell, occupying a thin layer 3–5 Å from the RNA. Distribution functions reveal that outer-sphere Mg2+ are positioned by electronegative atoms, hydration layers, and a preference for the major groove. Diffusion analysis suggests transient outer-sphere Mg2+ dynamics are glassy. Since outer-sphere Mg2+ ions account for most of the Mg2+ in our simulations, these ions may change the paradigm of Mg2+–RNA interactions. Rather than a few inner-sphere ions anchoring the RNA structure surrounded by a continuum of diffuse ions, we observe a layer of outer-sphere coordinated Mg2+ that is transiently bound but strongly coupled to the RNA.
Pierced Lasso Bundles Are a New Class of Knot-like Motifs
(Public Library of Science, 2014) Haglund, Ellinor; Sulkowska, Joanna I.; Noel, Jeffrey K.; Lammert, Heiko; Onuchic, José Nelson; Jennings, Patricia A.; Center for Theoretical Biological Physics
A four-helix bundle is a well-characterized motif often used as a target for designed pharmaceutical therapeutics and nutritional supplements. Recently, we discovered a new structural complexity within this motif created by a disulphide bridge in the long-chain helical bundle cytokine epileptic When oxidized, leptin contains a disulphide bridge creating a covalent-loop through which part of the polypeptide chain is threaded (as seen in knotted proteins). We explored whether other proteins contain a similar intriguing knot-like structure as in leptin and discovered 11 structurally homologous proteins in the PDB. We call this new helical family class the Pierced Lasso Bundle (PLB) and the knot-like threaded structural motif a Pierced Lasso (PL). In the current study, we use structure-based simulation to investigate the threading/folding mechanisms for all the PLBs along with three unthreaded homologs as the covalent loop (or lasso) in leptin is important in folding dynamics and activity. We find that the presence of a small covalent loop leads to a mechanism where structural elements slipknot to thread through the covalent loop. Larger loops use a piercing mechanism where the free terminal plugs through the covalent loop. Remarkably, the position of the loop as well as its size influences the native state dynamics, which can impact receptor binding and biological activity. This previously unrecognized complexity of knot-like proteins within the helical bundle family comprises a completely new class within the knot family, and the hidden complexity we unraveled in the PLBs is expected to be found in other protein structures outside the four-helix bundles. The insights gained here provide critical new elements for future investigation of this emerging class of proteins, where function and the energetic landscape can be controlled by hidden topology, and should be take into account in ab initio predictions of newly identified protein targets.
The Shadow Map: A General Contact Definition for Capturing the Dynamics of Biomolecular Folding and Function
(American Chemical Society, 2012) Noel, Jeffrey K.; Whitford, Paul C.; Onuchic, José N.; Center for Theoretical Biological Physics
Structure-based models (SBMs) are simplified models of the biomolecular dynamics that arise from funneled energy landscapes. We recently introduced an all-atom SBM that explicitly represents the atomic geometry of a biomolecule. While this initial study showed the robustness of the all-atom SBM Hamiltonian to changes in many of the energetic parameters, an important aspect, which has not been explored previously, is the definition of native interactions. In this study, we propose a general definition for generating atomically grained contact maps called “Shadow”. The Shadow algorithm initially considers all atoms within a cutoff distance and then, controlled by a screening parameter, discards the occluded contacts. We show that this choice of contact map is not only well behaved for protein folding, since it produces consistently cooperative folding behavior in SBMs but also desirable for exploring the dynamics of macromolecular assemblies since, it distributes energy similarly between RNAs and proteins despite their disparate internal packing. All-atom structure-based models employing Shadow contact maps provide a general framework for exploring the geometrical features of biomolecules, especially the connections between folding and function.
SMOG 2: A Versatile Software Package for Generating Structure-Based Models
(Public Library of Science, 2016) Noel, Jeffrey K.; Levi, Mariana; Raghunathan, Mohit; Lammert, Heiko; Hayes, Ryan L.; Onuchic, José N.; Whitford, Paul C.; Center for Theoretical Biological Physics
Molecular dynamics simulations with coarse-grained or simplified Hamiltonians have proven to be an effective means of capturing the functionally important long-time and large-length scale motions of proteins and RNAs. Originally developed in the context of protein folding, structure-based models (SBMs) have since been extended to probe a diverse range of biomolecular processes, spanning from protein and RNA folding to functional transitions in molecular machines. The hallmark feature of a structure-based model is that part, or all, of the potential energy function is defined by a known structure. Within this general class of models, there exist many possible variations in resolution and energetic composition. SMOG 2 is a downloadable software package that reads user-designated structural information and user-defined energy definitions, in order to produce the files necessary to use SBMs with high performance molecular dynamics packages: GROMACS and NAMD. SMOG 2 is bundled with XML-formatted template files that define commonly used SBMs, and it can process template files that are altered according to the needs of each user. This computational infrastructure also allows for experimental or bioinformatics-derived restraints or novel structural features to be included, e.g. novel ligands, prosthetic groups and post-translational/transcriptional modifications. The code and user guide can be downloaded at http://smog-server.org/smog2.
The Dominant Folding Route Minimizes Backbone Distortion in SH3
(Public Library of Science, 2012) Lammert, Heiko; Noel, Jeffrey K.; Onuchic, José N.; Center for Theoretical Biological Physics
Energetic frustration in protein folding is minimized by evolution to create a smooth and robust energy landscape. As a result the geometry of the native structure provides key constraints that shape protein folding mechanisms. Chain connectivity in particular has been identified as an essential component for realistic behavior of protein folding models. We study the quantitative balance of energetic and geometrical influences on the folding of SH3 in a structure-based model with minimal energetic frustration. A decomposition of the two-dimensional free energy landscape for the folding reaction into relevant energy and entropy contributions reveals that the entropy of the chain is not responsible for the folding mechanism. Instead the preferred folding route through the transition state arises from a cooperative energetic effect. Off-pathway structures are penalized by excess distortion in local backbone configurations and contact pair distances. This energy cost is a new ingredient in the malleable balance of interactions that controls the choice of routes during protein folding.

Browsing by Author "Noel, Jeffrey K."

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