scholarly journals Multimodal tubulin binding by the yeast kinesin-8, Kip3, underlies its motility and depolymerization

2021 ◽  
Author(s):  
Hugo Arellano-Santoyo ◽  
Rogelio A Hernandez-Lopez ◽  
Emma Stokasimov ◽  
Ray YR Wang ◽  
David Pellman ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Single Molecule ◽  
Conformational Changes ◽  
Intracellular Transport ◽  
Structural Features ◽  
Cellular Processes ◽  
Tubulin Binding ◽  
Dynamics Simulations ◽  
Spatiotemporal Control ◽  
Unique Ability

The microtubule (MT) cytoskeleton is central to cellular processes including axonal growth, intracellular transport, and cell division, all of which rely on precise spatiotemporal control of MT organization. Kinesin-8s play a key role in regulating MT length by combining highly processive directional motility with MT-end disassembly. However, how kinesin-8 switches between these two apparently opposing activities remains unclear. Here, we define the structural features underlying this molecular switch through cryo-EM analysis of the yeast kinesin-8, Kip3 bound to MTs, and molecular dynamics simulations to approximate the complex of Kip3 with the curved tubulin state found at the MT plus-end. By integrating biochemical and single-molecule biophysical assays, we identified specific intra- and intermolecular interactions that modulate processive motility and MT disassembly. Our findings suggest that Kip3 undergoes conformational changes in response to tubulin curvature that underlie its unique ability to interact differently with the MT lattice than with the MT-end.

Advances in the study of the mechanochemical coupling of kinesin

2018 ◽  
Vol 32 (18) ◽  
pp. 1840001 ◽  
Author(s):  
Ming Li ◽  
Zhong-Can Ou-Yang ◽  
Yao-Gen Shu
Keyword(s):  
Molecular Dynamics ◽  
Single Molecule ◽  
Intracellular Transport ◽  
Coordination Mechanism ◽  
Personal Perspective ◽  
Long Distance ◽  
Future Studies ◽  
Mechanochemical Coupling ◽  
Dynamics Simulations ◽  
Made In

Kinesin is a two-headed linear motor for intracellular transport. It can walk a long distance in a hand-over-hand manner along the track before detaching (i.e., high processivity), and it consumes one ATP molecule for each step (i.e., tight mechanochemical coupling). The mechanisms of the coordination of its two heads and the mechanochemical coupling are the central issues of numerous researches. A few advances have been made in recent decades, thanks to the development of single-molecule technologies and molecular dynamics simulations. In this paper, we review some progress of the studies on the kinematics, energetics, coordination mechanism, mechanochemical mechanism of kinesin. We also present a personal perspective on the future studies of kinesin.

scholarly journals A Topological Data Analytic Approach for Discovering Biophysical Signatures in Protein Dynamics

2021 ◽  
Author(s):  
Wai Shing Tang ◽  
Gabriel Monteiro da Silva ◽  
Henry Kirveslahti ◽  
Erin Skeens ◽  
Bibo Feng ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Protein Structures ◽  
Structural Features ◽  
Biologically Relevant ◽  
Visual Identification ◽  
Topological Features ◽  
Protein Ensembles ◽  
Dynamics Simulations

Identifying structural differences among proteins can be a non-trivial task. When contrasting ensembles of protein structures obtained from molecular dynamics simulations, biologically-relevant features can be easily overshadowed by spurious fluctuations. Here, we present SINATRA Pro, a computational pipeline designed to robustly identify topological differences between two sets of protein structures. Algorithmically, SINATRA Pro works by first taking in the 3D atomic coordinates for each protein snapshot and summarizing them according to their underlying topology. Statistically significant topological features are then projected back onto an user-selected representative protein structure, thus facilitating the visual identification of biophysical signatures of different protein ensembles. We assess the ability of SINATRA Pro to detect minute conformational changes in five independent protein systems of varying complexities. In all test cases, SINATRA Pro identifies known structural features that have been validated by previous experimental and computational studies, as well as novel features that are also likely to be biologically-relevant according to the literature. These results highlight SINATRA Pro as a promising method for facilitating the non-trivial task of pattern recognition in trajectories resulting from molecular dynamics simulations, with substantially increased resolution.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

scholarly journals Studies of Conformational Changes of Tubulin Induced by Interaction with Kinesin Using Atomistic Molecular Dynamics Simulations

2021 ◽  
Vol 22 (13) ◽  
pp. 6709
Author(s):  
Xiao-Xuan Shi ◽  
Peng-Ye Wang ◽  
Hong Chen ◽  
Ping Xie
Keyword(s):  
Molecular Dynamics ◽  
High Resolution ◽  
Binding Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Weak Interactions ◽  
Molecular Motor ◽  
Structural Data ◽  
Calculated Binding Energy ◽  
Dynamics Simulations

The transition between strong and weak interactions of the kinesin head with the microtubule, which is regulated by the change of the nucleotide state of the head, is indispensable for the processive motion of the kinesin molecular motor on the microtubule. Here, using all-atom molecular dynamics simulations, the interactions between the kinesin head and tubulin are studied on the basis of the available high-resolution structural data. We found that the strong interaction can induce rapid large conformational changes of the tubulin, whereas the weak interaction cannot. Furthermore, we found that the large conformational changes of the tubulin have a significant effect on the interaction of the tubulin with the head in the weak-microtubule-binding ADP state. The calculated binding energy of the ADP-bound head to the tubulin with the large conformational changes is only about half that of the tubulin without the conformational changes.

scholarly journals Computational Design of Macrocyclic Binders of S100B(ββ): Novel Peptide Theranostics

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 721
Author(s):  
Srinivasaraghavan Kannan ◽  
Pietro G. A. Aronica ◽  
Thanh Binh Nguyen ◽  
Jianguo Li ◽  
Chandra S. Verma
Keyword(s):  
Molecular Dynamics ◽  
Computational Design ◽  
Diagnostic Tools ◽  
Stapled Peptides ◽  
Altered Expression ◽  
Cellular Processes ◽  
High Affinity ◽  
Limited Success ◽  
Dynamics Simulations ◽  
Partner Proteins

S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ββ) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ββ) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ββ) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ββ) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ββ) but also to disrupt the interactions of S100B(ββ) with partner proteins which drive disease progression, thus serving as novel therapeutics.

Cluster, Surface and Bulk Properties of ZnCd Binary Alloys: Molecular-Dynamics Simulations

2005 ◽  
Vol 502 ◽  
pp. 51-56 ◽  
Author(s):  
Sakir Erkoc
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Density Functional ◽  
Structural Features ◽  
Bulk Materials ◽  
Bulk Properties ◽  
Atom Clusters ◽  
Dynamics Simulations ◽  
Mixed Clusters ◽  
Stable Structures

The structural and electronic properties of isolated neutral ZnmCdn clusters for m+n £ 3 have been investigated by performing density functional theory calculations at B3LYP level. The optimum geometries, vibrational frequencies, electronic structures, and the possible dissosiation channels of the clusters considered have been obtained. An empirical many-body potential energy function (PEF), which comprices two- and three-body atomic interactions, has been developed to investigate the structural features and energetics of ZnmCdn (m+n=3,4) microclusters. The most stable structures were found to be triangular for the three-atom clusters and tetrahedral for the four-atom clusters. On the other hand, the structural features and energetics of Znn-mCdm (n=7,8) microclusters, and Zn50, Cd50, Zn25Cd25, Zn12Cd38, and Zn38Cd12 nanoparticles have been investigated by performing molecular-dynamics computer simulations using the developed PEF. The most stable structures were found to be compact and three-dimensional for all elemental and mixed clusters. An interesting structural feature of the mixed clusters is that Zn and Cd atoms do not mix in mixed clusters, they come together almost without mixing. Surface and bulk properties of Zn, Cd, and ZnCd systems have been investigated too by performing molecular-dynamics simulations using the developed PEF. Surface reconstruction and multilayer relaxation on clean surfaces, adatom on surface, substitutional atom on surface and bulk materials, and vacancy on surface and bulk materials have been studied extensively.

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