R-3 Repository :: Browsing by Author "Wolynes, Peter G."

Browsing by Author "Wolynes, Peter G."

Now showing 1 - 20 of 53

A structural dynamics model for how CPEB3 binding to SUMO2 can regulate translational control in dendritic spines
(Public Library of Science, 2022) Gu, Xinyu; Schafer, Nicholas P.; Bueno, Carlos; Lu, Wei; Wolynes, Peter G.; Center for Theoretical Biological Physics
A prion-like RNA-binding protein, CPEB3, can regulate local translation in dendritic spines. CPEB3 monomers repress translation, whereas CPEB3 aggregates activate translation of its target mRNAs. However, the CPEB3 aggregates, as long-lasting prions, may raise the problem of unregulated translational activation. Here, we propose a computational model of the complex structure between CPEB3 RNA-binding domain (CPEB3-RBD) and small ubiquitin-like modifier protein 2 (SUMO2). Free energy calculations suggest that the allosteric effect of CPEB3-RBD/SUMO2 interaction can amplify the RNA-binding affinity of CPEB3. Combining with previous experimental observations on the SUMOylation mode of CPEB3, this model suggests an equilibrium shift of mRNA from binding to deSUMOylated CPEB3 aggregates to binding to SUMOylated CPEB3 monomers in basal synapses. This work shows how a burst of local translation in synapses can be silenced following a stimulation pulse, and explores the CPEB3/SUMO2 interplay underlying the structural change of synapses and the formation of long-term memories.
Active patterning and asymmetric transport in a model actomyosin network
(AIP Publishing LLC, 2013) Wang, Shenshen; Wolynes, Peter G.; Center for Theoretical Biological Physics
Cytoskeletal networks, which are essentially motor-filament assemblies, play a major role in many developmental processes involving structural remodeling and shape changes. These are achieved by nonequilibrium self-organization processes that generate functional patterns and drive intracellular transport. We construct a minimal physical model that incorporates the coupling between nonlinear elastic responses of individual filaments and force-dependent motor action. By performing stochastic simulations we show that the interplay of motor processes, described as driving anti-correlated motion of the network vertices, and the network connectivity, which determines the percolation character of the structure, can indeed capture the dynamical and structural cooperativity which gives rise to diverse patterns observed experimentally. The buckling instability of individual filaments is found to play a key role in localizing collapse events due to local force imbalance. Motor-driven buckling-induced node aggregation provides a dynamic mechanism that stabilizes the two-dimensional patterns below the apparent static percolation limit. Coordinated motor action is also shown to suppress random thermal noise on large time scales, the two-dimensional configuration that the system starts with thus remaining planar during the structural development. By carrying out similar simulations on a three-dimensional anchored network, we find that the myosin-driven isotropic contraction of a well-connected actin network, when combined with mechanical anchoring that confers directionality to the collective motion, may represent a novel mechanism of intracellular transport, as revealed by chromosome translocation in the starfish oocyte.
Aging, Jamming, and the Limits of Stability of Amorphous Solids
(American Chemical Society, 2018) Lubchenko, Vassiliy; Wolynes, Peter G.; Center for Theoretical Biological Physics
Apart from not having crystallized, supercooled liquids can be considered as being properly equilibrated and thus can be described by a few thermodynamic control variables. In contrast, glasses and other amorphous solids can be arbitrarily far away from equilibrium and require a description of the history of the conditions under which they formed. In this paper we describe how the locality of interactions intrinsic to finite-dimensional systems affects the stability of amorphous solids far off equilibrium. Our analysis encompasses both structural glasses formed by cooling and colloidal assemblies formed by compression. A diagram outlining regions of marginal stability can be adduced which bears some resemblance to the quasi-equilibrium replica meanfield theory phase diagram of hard sphere glasses in high dimensions but is distinct from that construct in that the diagram describes not true phase transitions but kinetic transitions that depend on the preparation protocol. The diagram exhibits two distinct sectors. One sector corresponds to amorphous states with relatively open structures, the other to high density, more closely packed ones. The former transform rapidly owing to there being motions with no free energy barriers; these motions are string-like locally. In the dense region, amorphous systems age via compact activated reconfigurations. The two regimes correspond, in equilibrium, to the collisional or uniform liquid and the so-called landscape regime, respectively. These are separated by a spinodal line of dynamical crossovers. Owing to the rigidity of the surrounding matrix in the landscape, high-density part of the diagram, a sufficiently rapid pressure quench adds compressive energy which also leads to an instability toward string-like motions with near vanishing barriers. Conversely, a dilute collection of rigid particles, such as a colloidal suspension leads, when compressed, to a spatially heterogeneous structure with percolated mechanically stable regions. This jamming corresponds to the onset of activation when the spinodal line is traversed from the low density side. We argue that a stable glass made of sufficiently rigid particles can also be viewed as exhibiting sporadic and localized buckling instabilities that result in local jammed structures. The lines of instability we discuss resemble the Gardner transition of meanfield systems but, in contrast, do not result in true criticality owing to being short-circuited by activated events. The locally marginally stable modes of motion in amorphous solids correspond to secondary relaxation processes in structural glasses. Their relevance to the low temperature anomalies in glasses is also discussed.
An intrinsically disordered transcription activation domain increases the DNA binding affinity and reduces the specificity of NFκB p50/RelA
(Elsevier, 2022) Baughman, Hannah E.R.; Narang, Dominic; Chen, Wei; Villagrán Suárez, Amalia C.; Lee, Joan; Bachochin, Maxwell J.; Gunther, Tristan R.; Wolynes, Peter G.; Komives, Elizabeth A.; Center for Theoretical Biological Physics
Many transcription factors contain intrinsically disordered transcription activation domains (TADs), which mediate interactions with coactivators to activate transcription. Historically, DNA-binding domains and TADs have been considered as modular units, but recent studies have shown that TADs can influence DNA binding. Whether these results can be generalized to more TADs is not clear. Here, we biophysically characterized the NFκB p50/RelA heterodimer including the RelA TAD and investigated the TAD’s influence on NFκB–DNA interactions. In solution, we show the RelA TAD is disordered but compact, with helical tendency in two regions that interact with coactivators. We determined that the presence of the TAD increased the stoichiometry of NFκB–DNA complexes containing promoter DNA sequences with tandem κB recognition motifs by promoting the binding of NFκB dimers in excess of the number of κB sites. In addition, we measured the binding affinity of p50/RelA for DNA containing tandem κB sites and single κB sites. While the presence of the TAD enhanced the binding affinity of p50/RelA for all κB sequences tested, it also increased the affinity for nonspecific DNA sequences by over 10-fold, leading to an overall decrease in specificity for κB DNA sequences. In contrast, previous studies have generally reported that TADs decrease DNA-binding affinity and increase sequence specificity. Our results reveal a novel function of the RelA TAD in promoting binding to nonconsensus DNA, which sheds light on previous observations of extensive nonconsensus DNA binding by NFκB in vivo in response to strong inflammatory signals.
Anomalous diffusion, spatial coherence, and viscoelasticity from the energy landscape of human chromosomes
(National Academy of Sciences of the United States of America, 2018) Di Pierro, Michele; Potoyan, Davit A.; Wolynes, Peter G.; Onuchic, José Nelson
The nucleus of a eukaryotic cell is a nonequilibrium system where chromatin is subjected to active processes that continuously rearrange it over the cell's life cycle. Tracking the motion of chromosomal loci provides information about the organization of the genome and the physical processes shaping that organization. Optical experiments report that loci move with subdiffusive dynamics and that there is spatially coherent motion of the chromatin. We recently showed that it is possible to predict the 3D architecture of genomes through a physical model for chromosomes that accounts for the biochemical interactions mediated by proteins and regulated by epigenetic markers through a transferable energy landscape. Here, we study the temporal dynamics generated by this quasi-equilibrium energy landscape assuming Langevin dynamics at an effective temperature. Using molecular dynamics simulations of two interacting human chromosomes, we show that the very same interactions that account for genome architecture naturally reproduce the spatial coherence, viscoelasticity, and the subdiffusive behavior of the motion in interphase chromosomes as observed in numerous experiments. The agreement between theory and experiments suggests that even if active processes are involved, an effective quasi-equilibrium landscape model can largely mimic their dynamical effects.
Assemblies of calcium/calmodulin-dependent kinase II with actin and their dynamic regulation by calmodulin in dendritic spines
(National Academy of Sciences, 2019) Wang, Qian; Chen, Mingchen; Schafer, Nicholas P.; Bueno, Carlos; Song, Sarah S.; Hudmon, Andy; Wolynes, Peter G.; Waxham, M. Neal; Cheung, Margaret S.
The structural dynamics of the dendritic synapse, arising from the remodeling of actin cytoskeletons, has been widely associated with memory and cognition. The remodeling is regulated by intracellular Ca2+ levels. Under low Ca2+ concentration, actin filaments are bundled by a calcium signaling protein, CaMKII. When the Ca2+ concentration is raised, CaMKII dissociates from actin and opens the window for actin remodeling. At present, the molecular details of the actin bundling and regulation are elusive. Herein we use experimental tools along with molecular simulations to construct a model of how CaMKII bundles actin and how the CaMKII–actin architecture is regulated by Ca2+ signals. In this way, our results explain how Ca2+ signals ultimately change the structure of the dendritic synapse.
Chemical physics of protein folding
(2012-10-30) Wolynes, Peter G.; Eaton, William A.; Fersht, Alan R.; Center for Theoretical Biological Physics; National Academy of Sciences
Coarse-Grained Modeling and Molecular Dynamics Simulations of Ca2+-Calmodulin
(Frontiers, 2021) Nde, Jules; Zhang, Pengzhi; Ezerski, Jacob C.; Lu, Wei; Knapp, Kaitlin; Wolynes, Peter G.; Cheung, Margaret S.; Center for Theoretical Biological Physics
Calmodulin (CaM) is a calcium-binding protein that transduces signals to downstream proteins through target binding upon calcium binding in a time-dependent manner. Understanding the target binding process that tunes CaM’s affinity for the calcium ions (Ca2+), or vice versa, may provide insight into how Ca2+-CaM selects its target binding proteins. However, modeling of Ca2+-CaM in molecular simulations is challenging because of the gross structural changes in its central linker regions while the two lobes are relatively rigid due to tight binding of the Ca2+ to the calcium-binding loops where the loop forms a pentagonal bipyramidal coordination geometry with Ca2+. This feature that underlies the reciprocal relation between Ca2+ binding and target binding of CaM, however, has yet to be considered in the structural modeling. Here, we presented a coarse-grained model based on the Associative memory, Water mediated, Structure, and Energy Model (AWSEM) protein force field, to investigate the salient features of CaM. Particularly, we optimized the force field of CaM and that of Ca2+ ions by using its coordination chemistry in the calcium-binding loops to match with experimental observations. We presented a “community model” of CaM that is capable of sampling various conformations of CaM, incorporating various calcium-binding states, and carrying the memory of binding with various targets, which sets the foundation of the reciprocal relation of target binding and Ca2+ binding in future studies.
Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1–42) and Amyloid Beta(1–40)
(American Chemical Society, 2017) Zheng, Weihua; Tsai, Min-Yeh; Wolynes, Peter G.
Using a predictive coarse-grained protein force field, we compute and compare the free energy landscapes and relative stabilities of amyloid-β protein (1–42) and amyloid-β protein (1–40) in their monomeric and oligomeric forms up to the octamer. At the same concentration, the aggregation free energy profile of Aβ42 is more downhill, with a computed solubility that is about 10 times smaller than that of Aβ40. At a concentration of 40 μM, the clear free energy barrier between the pre-fibrillar tetramer form and the fibrillar pentamer in the Aβ40 aggregation landscape disappears for Aβ42, suggesting that the Aβ42 tetramer has a more diverse structural range. To further compare the landscapes, we develop a cluster analysis based on the structural similarity between configurations and use it to construct an oligomerization map that captures the paths of easy interconversion between different but structurally similar states of oligomers for both species. A taxonomy of the oligomer species based on β-sheet stacking topologies is proposed. The comparison of the two oligomerization maps highlights several key differences in the landscapes that can be attributed to the two additional C-terminal residues that Aβ40 lacks. In general, the two terminal residues strongly stabilize the oligomeric structures for Aβ42 relative to Aβ40, and greatly facilitate the conversion from pre-fibrillar trimers to fibrillar tetramers.
Computationally exploring the mechanism of bacteriophage T7 gp4 helicase translocating along ssDNA
(National Academy of Sciences, 2022) Jin, Shikai; Bueno, Carlos; Lu, Wei; Wang, Qian; Chen, Mingchen; Chen, Xun; Wolynes, Peter G.; Gao, Yang; Center for Theoretical Biological Physics
Bacteriophage T7 gp4 helicase has served as a model system for understanding mechanisms of hexameric replicative helicase translocation. The mechanistic basis of how nucleoside 5′-triphosphate hydrolysis and translocation of gp4 helicase are coupled is not fully resolved. Here, we used a thermodynamically benchmarked coarse-grained protein force field, Associative memory, Water mediated, Structure and Energy Model (AWSEM), with the single-stranded DNA (ssDNA) force field 3SPN.2C to investigate gp4 translocation. We found that the adenosine 5′-triphosphate (ATP) at the subunit interface stabilizes the subunit–subunit interaction and inhibits subunit translocation. Hydrolysis of ATP to adenosine 5′-diphosphate enables the translocation of one subunit, and new ATP binding at the new subunit interface finalizes the subunit translocation. The LoopD2 and the N-terminal primase domain provide transient protein–protein and protein–DNA interactions that facilitate the large-scale subunit movement. The simulations of gp4 helicase both validate our coarse-grained protein–ssDNA force field and elucidate the molecular basis of replicative helicase translocation.
De novo prediction of human chromosome structures: Epigenetic marking patterns encode genome architecture
(National Academy of Sciences, 2017) Di Pierro, Michele; Cheng, Ryan R.; Aiden, Erez Lieberman; Wolynes, Peter G.; Onuchic, José N.; Center for Theoretical Biological Physics
Inside the cell nucleus, genomes fold into organized structures that are characteristic of cell type. Here, we show that this chromatin architecture can be predicted de novo using epigenetic data derived from chromatin immunoprecipitation-sequencing (ChIP-Seq). We exploit the idea that chromosomes encode a 1D sequence of chromatin structural types. Interactions between these chromatin types determine the 3D structural ensemble of chromosomes through a process similar to phase separation. First, a neural network is used to infer the relation between the epigenetic marks present at a locus, as assayed by ChIP-Seq, and the genomic compartment in which those loci reside, as measured by DNA-DNA proximity ligation (Hi-C). Next, types inferred from this neural network are used as an input to an energy landscape model for chromatin organization [Minimal Chromatin Model (MiChroM)] to generate an ensemble of 3D chromosome conformations at a resolution of 50 kilobases (kb). After training the model, dubbed Maximum Entropy Genomic Annotation from Biomarkers Associated to Structural Ensembles (MEGABASE), on odd-numbered chromosomes, we predict the sequences of chromatin types and the subsequent 3D conformational ensembles for the even chromosomes. We validate these structural ensembles by using ChIP-Seq tracks alone to predict Hi-C maps, as well as distances measured using 3D fluorescence in situ hybridization (FISH) experiments. Both sets of experiments support the hypothesis of phase separation being the driving process behind compartmentalization. These findings strongly suggest that epigenetic marking patterns encode sufficient information to determine the global architecture of chromosomes and that de novo structure prediction for whole genomes may be increasingly possible.
Design and Structural Characterization of Self-Assembling Triple Helical Heterotrimers
(2013-06-05) Fallas Valverde, Jorge; Hartgerink, Jeffrey D.; Wolynes, Peter G.; Tao, Yizhi Jane
Design of self-assembling ABC-type collagen triple helical heterotrimers is challenging due to the number of competing species that can be formed in ternary mixture of peptides with a high propensity to fold into triple helices and the fact that well understood rules for pair-wise amino acid stabilization of the canonical collagen triple helix have remained elusive. Given the required one amino acid stagger between adjacent peptide strands in this fold, a ternary mixture of peptides can form as many as 27 triple helices with unique composition or register. Previously we have demonstrated that electrostatic interactions can be used to bias the helix population towards a desired target but the presence of competing states in mixtures has remained an outstanding problem. In this work we use high-resolution structural biology techniques to do a detailed study of stabilizing pair-wise interactions between positively and negatively charged amino acids in triple helices. Two types of contacts with distinct sequence requirements depending on the relative stagger of the interacting chains are observed: axial and lateral. Such register-specific interactions are crucial for the understanding of the registration process of collagens and the overall stability of proteins in this family. Using this knowledge we developed distinct design strategies to improve the specificity of our designed systems towards the desired ABC heterotrimeric target state. We validate our strategies through the synthesis and characterization of the designed sequences and show that they self-assemble into a highly stable ABC triple helices with control over composition in the case of the rational approach and with control over both composition and register in the case of the computational approach.
Design of Heterotrimeric Collagen Triple Helices
(2014-04-24) Jalan, Abhishek; Hartgerink, Jeffrey D.; Wolynes, Peter G.; Tao, Yizhi Jane
Select loci in native collagen display clusters of contiguous amino acids that recognize a diverse array of extracellular matrix (ECM) and blood serum proteins critical for homeostasis and hemostasis. The mechanism of collagen binding to these proteins has primarily been elucidated using short peptides, called collagen mimetic peptides (CMPs), that independently fold into the so called homotrimeric collagen triple helices, where all three peptide chains have identical amino acid sequence. However, the homotrimer binding mechanism cannot be extrapolated to explain protein binding in AAB and ABC-type heterotrimeric collagens that contain either two or three unique polypeptide chains without significant speculation. Given the requirement of a one amino acid offset between the peptide chains in a collagen triple helix, a mixture of two or three unique peptides can self-assemble into 8 and 27 competing triple helices, respectively. Heterotrimeric CMPs have remained synthetically inaccessible due to the challenge associated with introducing bias in this ensemble of competing states. Previously, Hartgerink lab employed axial Lys – Asp / Glu salt-bridges to successfully self-assemble an ABC heterotrimer. Here, we extend this paradigm to successfully demonstrate the design of a proof-of-principle AAB heterotrimer. Four AAB heterotrimers, each carrying unpaired Lys, Asp or Glu and a combination of Lys – Asp or Lys – Glu axial salt-bridges, were designed. Of these, only the heterotrimer containing unpaired Glu and a combination of Lys – Asp as well as Lys – Glu salt-bridges successfully self-assembled into an AAB heterotrimer. Next, a general methodology to self-assemble AAB heterotrimers containing the α2β1 and α1β1-integrin recognition sequences from collagen I and IV, respectively, and the matrix metalloproteinase-1 cleavage sequence from collagen I was developed. The protein recognition sequences were included as guests in a host peptide sequence containing a network of salt-bridges that bias the ensemble of competing triple helices to the desired AAB heterotrimer. Successful self-assembly of heterotrimers across multiple guest sequences was observed, which demonstrates the wide applicability of the host sequence design. In future, binding of these heterotrimers to the ECM and blood serum proteins has the potential to unravel the mechanism of disease evolution across multiple disease settings. We also extended the salt-bridge based design paradigm to synthesize a new class of CMP constructs. Hydroxyproline-free collagen triple helices are lucrative for expression in bacterial systems. Using a combination of Lys – Asp and Lys – Glu salt-bridges, a hydroxyproline-free ABC collagen heterotrimer was successfully designed. Remarkably, this ABC heterotrimer was stable despite one the peptides containing no proline or hydroxyproline, a requirement previously thought to be critical for stability. Additionally, an ABC heterotrimer containing a non-canonical four residue offset between the peptide chains was designed. In this heterotrimer, the non-covalent interactions at the termini are unsatisfied which renders them “sticky” to further assembly. This design lays the groundwork to create longer and therefore, stickier offsets to facilitate self-assembly of collagen-mimetic nanofibers.
Dichotomous noise models of gene switches
(AIP Publishing LLC., 2015) Potoyan, Davit A.; Wolynes, Peter G.; Center for Theoretical Biological Physics
Molecular noise in gene regulatory networks has two intrinsic components, one part being due to fluctuations caused by the birth and death of protein or mRNA molecules which are often present in small numbers and the other part arising from gene state switching, a single molecule event. Stochastic dynamics of gene regulatory circuits appears to be largely responsible for bifurcations into a set of multi-attractor states that encode different cell phenotypes. The interplay of dichotomous single molecule gene noise with the nonlinear architecture of genetic networks generates rich and complex phenomena. In this paper, we elaborate on an approximate framework that leads to simple hybrid multi-scale schemes well suited for the quantitative exploration of the steady state properties of large-scale cellular genetic circuits. Through a path sum based analysis of trajectory statistics, we elucidate the connection of these hybrid schemes to the underlying master equation and provide a rigorous justification for using dichotomous noise based models to study genetic networks. Numerical simulations of circuit models reveal that the contribution of the genetic noise of single molecule origin to the total noise is significant for a wide range of kinetic regimes.
Dynamical Heterogeneity of the Glassy State
(2014-04-24) Wisitsorasak, Apiwat; Wolynes, Peter G.; Levy, Eugene H.; Levine, Herbert
The understanding and the complete description of the glass transition are impeded by the complexity of nature of the glass. Parts of this complexity come from the emergence of long-lived inherent structures of a liquid at a temperature below which the activated reconfiguration events play a dominant role. Molecules in a glass change their locations through the activated process at a rate which varies throughout the glass owing to these local and aperiodic structures. Motions in one location also cause or relieve constrains, thereby altering the rate of transitions of neighboring regions. The key to understanding this problem is the interplay between the activated events that generate mobility and the transport of mobility. In the following we explore fluctuating mobility generation and transport in glasses to understand the dynamics of the glassy state within the framework of the random first order transition theory of glass. Fluctuating mobility generation and transport in the glass that arise from there being a distribution of local stability and thus effective temperature are treated by numerically solving stochastic continuum equations for mobility and fictive temperature fields. Fluctuating spatiotemporal structures in aging and rejuvenating glasses lead to dynamical heterogeneity in glasses with characteristics that are distinct from those found in the equilibrium liquid. We illustrate in this thesis how the heterogeneity in glasses gives rises of a non-Gaussian distribution of activation free energies, the stretching exponent, and the growth of characteristic lengths. These are studied along with the four-point dynamic correlation function. Asymmetric thermodynamic responses upon heating and cooling are also predicted to be the results of the heterogeneity and the out-of-equilibrium behavior of glasses below the glass transition temperature. Moreover the dynamical heterogeneity can lead to a growth front of mobility in rejuvenating glasses that emanates from the surface where stable glasses are heated. Noticeably bimodal distributions of local fictive temperatures in aging glasses are also investigate. This result explains recent experimental observations that have been interpreted as coming from these being two distinct equilibration mechanisms in glasses. Finally we study the mechanical properties of glasses. The remarkable strength of glasses is examined using the random first order transition theory. The theory predicts that the strength not only depends on the elastic modulus but also depends on the amount of configurational energy frozen in when the glass is prepared. The stress catalysis of cooperative rearrangements of the same type as those responsible for the supercooled liquid's high viscosity account quantitatively for the measured strength of a range of metallic glasses, silica and a polymer glass.
Energy landscape underlying spontaneous insertion and folding of an alpha-helical transmembrane protein into a bilayer
(Springer Nature, 2018) Lu, Wei; Schafer, Nicholas P.; Wolynes, Peter G.
Membrane protein folding mechanisms and rates are notoriously hard to determine. A recent force spectroscopy study of the folding of an α-helical membrane protein, GlpG, showed that the folded state has a very high kinetic stability and a relatively low thermodynamic stability. Here, we simulate the spontaneous insertion and folding of GlpG into a bilayer. An energy landscape analysis of the simulations suggests that GlpG folds via sequential insertion of helical hairpins. The rate-limiting step involves simultaneous insertion and folding of the final helical hairpin. The striking features of GlpG's experimentally measured landscape can therefore be explained by a partially inserted metastable state, which leads us to a reinterpretation of the rates measured by force spectroscopy. Our results are consistent with the helical hairpin hypothesis but call into question the two-stage model of membrane protein folding as a general description of folding mechanisms in the presence of bilayers.
Exploring Amyloid-B Aggregation Pathways and Identifying Key Differences Between AB40, AB42, and Known Mutants
(2021-12-03) Knapp, Kaitlin; Wolynes, Peter G.
First described in 1906 by Alois Alzheimer, who reported the presence of senile plaques and neurofibrillary tangles in the brain tissue of a sufferer, Alzheimer’s disease is now the most common form of dementia. Many years later it was determined that the hallmark senile plaques were composed of aggregated peptide fragments, referred to as amyloid beta. Like other amyloids, these fragments can exist as highly disordered monomers, disordered soluble oligomers, and highly ordered macroscopic fibrils. Despite decades of research, many open questions remain in regard to the role of amyloid beta in the pathology of Alzheimer’s disease. In this dissertation, molecular dynamics simulations, in complement with experimental results, will be employed to address a few of these questions. In particular, a molecular level picture is developed elucidating the differences in aggregation rates between the two most common isoforms of the protein, providing evidence of possible pharmaceutical targets. Data related to the conformational search undertaken by amyloid beta monomers will be analyzed, revealing a possible connection between the secondary structure of wild type and mutated monomers and their observed fibrilization rates. Finally, the fibril elongation behavior of amyloid beta containing a single-point mutation associated with a devastating form of Alzheimer’s disease will be investigated to gain insight into the physicochemical properties driving its distinct clinical presentations. The resulting conclusions of these efforts lay the foundation for further experiments which could address critical factors related to the pathological role of aggregation rates, different early oligomerization behavior, and sources of neurotoxicity.
Exploring chromosomal structural heterogeneity across multiple cell lines
(eLife, 2020) Cheng, Ryan R.; Contessoto, Vinícius G.; Aiden, Erez Lieberman; Wolynes, Peter G.; Di Pierro, Michele; Onuchic, José Nelson; Center for Theoretical Biological Physics
Using computer simulations, we generate cell-specific 3D chromosomal structures and compare them to recently published chromatin structures obtained through microscopy. We demonstrate using machine learning and polymer physics simulations that epigenetic information can be used to predict the structural ensembles of multiple human cell lines. Theory predicts that chromosome structures are fluid and can only be described by an ensemble, which is consistent with the observation that chromosomes exhibit no unique fold. Nevertheless, our analysis of both structures from simulation and microscopy reveals that short segments of chromatin make two-state transitions between closed conformations and open dumbbell conformations. Finally, we study the conformational changes associated with the switching of genomic compartments observed in human cell lines. The formation of genomic compartments resembles hydrophobic collapse in protein folding, with the aggregation of denser and predominantly inactive chromatin driving the positioning of active chromatin toward the surface of individual chromosomal territories.
Fluctuating mobility generation and transport in glasses
(American Physical Society, 2013) Wisitsorasak, Apiwat; Wolynes, Peter G.
In the context of the random first order transition theory we use an extended mode coupling theory of the glass transition that includes activated events to account for spatiotemporal structures in rejuvenating glasses. We numerically solve fluctuating dynamical equations for mobility and fictive temperature fields which capture both mobility generation through activated events and facilitation effects. Upon rejuvenating, a source of high mobility at a glass surface initiates a growth front of mobility which propagates into the unstable low mobility region. The speed of the front quantitatively agrees with experiments on the rejuvenation of ultrastable glasses, which “melt” from their surface.
Folding, Binding, Misfolding and Aggregation with AWSEM
(2014-04-23) Schafer, Nicholas Peter; Wolynes, Peter G.; Onuchic, Jose N.; Clementi, Cecilia
This thesis discusses our recent results using the Associative-memory, Water-mediated, Structure and Energy Model (AWSEM), an optimized, coarse-grained molecular dynamics protein folding model, to fold, bind, and predict the misfolding behavior of proteins. AWSEM is capable of performing de novo structure prediction on small alpha-helical protein domains and predict the binding interfaces of homo- and hetero-dimers. More recent work demonstrates how the misfolding behavior of tandem constructs in AWSEM is consistent with crucial aspects of ensemble and single molecule experiments on the aggregation and misfolding of these constructs. The first chapter is a review of the energy landscape theory of protein folding as it applies to the problem of protein structure prediction, and more specifically how energy landscape theory and the principle of minimal frustration can be used to optimize parameters of coarse-grained protein folding simulation models. The subsequent four chapters are reports of novel research performed with one such model.

Browsing by Author "Wolynes, Peter G."

Results Per Page

Sort Options