A coarse-grained model of the expansion of the human rhinovirus 2 capsid reveals insights in genome release

Human rhinoviruses are causative agents of the common cold. In order to release their RNA genome into the host during a viral infection, these small viruses must undergo conformational changes in their capsids, whose detailed mechanism is strictly related to the process of RNA extrusion, which has been only partially elucidated. We study here a mathematical model for the structural transition between the native particle of human rhinovirus type 2 and its expanded form, viewing the process as an energy cascade, i.e. a sequence of metastable states with decreasing energy connected by minimum energy paths. We explore several transition pathways and discuss their implications for the RNA exit process.

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Simulating the function of sodium/proton antiporters

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1516881112 ◽

2015 ◽

Vol 112 (40) ◽

pp. 12378-12383 ◽

Cited By ~ 14

Author(s):

Raphael Alhadeff ◽

Arieh Warshel

Keyword(s):

Conformational Changes ◽

Molecular Basis ◽

Molecular Level ◽

Structural Information ◽

Coarse Grained ◽

Charged State ◽

Transport Models ◽

Coarse Grained Model ◽

Effective Transport ◽

Molecular Origin

The molecular basis of the function of transporters is a problem of significant importance, and the emerging structural information has not yet been converted to a full understanding of the corresponding function. This work explores the molecular origin of the function of the bacterial Na+/H+ antiporter NhaA by evaluating the energetics of the Na+ and H+ movement and then using the resulting landscape in Monte Carlo simulations that examine two transport models and explore which model can reproduce the relevant experimental results. The simulations reproduce the observed transport features by a relatively simple model that relates the protein structure to its transporting function. Focusing on the two key aspartic acid residues of NhaA, D163 and D164, shows that the fully charged state acts as an Na+ trap and that the fully protonated one poses an energetic barrier that blocks the transport of Na+. By alternating between the former and latter states, mediated by the partially protonated protein, protons, and Na+ can be exchanged across the membrane at 2:1 stoichiometry. Our study provides a numerical validation of the need of large conformational changes for effective transport. Furthermore, we also yield a reasonable explanation for the observation that some mammalian transporters have 1:1 stoichiometry. The present coarse-grained model can provide a general way for exploring the function of transporters on a molecular level.

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Computation of conformational transitions in proteins by virtual atom molecular mechanics as validated in application to adenylate kinase

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0907684106 ◽

2009 ◽

Vol 106 (37) ◽

pp. 15673-15678 ◽

Cited By ~ 19

Author(s):

Anil Korkut ◽

Wayne A. Hendrickson

Keyword(s):

Molecular Mechanics ◽

Conformational Changes ◽

Adenylate Kinase ◽

Normal Modes ◽

Conformational Transitions ◽

The Other ◽

Coarse Grained ◽

Knowledge Based ◽

Comprehensive Knowledge ◽

Transition Pathways

Many proteins function through conformational transitions between structurally disparate states, and there is a need to explore transition pathways between experimentally accessible states by computation. The sizes of systems of interest and the scale of conformational changes are often beyond the scope of full atomic models, but appropriate coarse-grained approaches can capture significant features. We have designed a comprehensive knowledge-based potential function based on a Cα representation for proteins that we call the virtual atom molecular mechanics (VAMM) force field. Here, we describe an algorithm for using the VAMM potential to describe conformational transitions, and we validate this algorithm in application to a transition between open and closed states of adenylate kinase (ADK). The VAMM algorithm computes normal modes for each state and iteratively moves each structure toward the other through a series of intermediates. The move from each side at each step is taken along that normal mode showing greatest engagement with the other state. The process continues to convergence of terminal intermediates to within a defined limit—here, a root-mean-square deviation of 1 Å. Validations show that the VAMM algorithm is highly effective, and the transition pathways examined for ADK are compatible with other structural and biophysical information. We expect that the VAMM algorithm can address many biological systems.

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Molecular determinants of the interactions between proteins and ssDNA

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1416355112 ◽

2015 ◽

Vol 112 (16) ◽

pp. 5033-5038 ◽

Cited By ~ 18

Author(s):

Garima Mishra ◽

Yaakov Levy

Keyword(s):

Conformational Changes ◽

Protein Interactions ◽

Binding Pocket ◽

Dna Bases ◽

Coarse Grained ◽

Binding Modes ◽

Ssdna Binding ◽

Coarse Grained Model ◽

Molecular Determinants ◽

Ssdna Binding Proteins

ssDNA binding proteins (SSBs) protect ssDNA from chemical and enzymatic assault that can derail DNA processing machinery. Complexes between SSBs and ssDNA are often highly stable, but predicting their structures is challenging, mostly because of the inherent flexibility of ssDNA and the geometric and energetic complexity of the interfaces that it forms. Here, we report a newly developed coarse-grained model to predict the structure of SSB–ssDNA complexes. The model is successfully applied to predict the binding modes of six SSBs with ssDNA strands of lengths of 6–65 nt. In addition to charge–charge interactions (which are often central to governing protein interactions with nucleic acids by means of electrostatic complementarity), an essential energetic term to predict SSB–ssDNA complexes is the interactions between aromatic residues and DNA bases. For some systems, flexibility is required from not only the ssDNA but also, the SSB to allow it to undergo conformational changes and the penetration of the ssDNA into its binding pocket. The association mechanisms can be quite varied, and in several cases, they involve the ssDNA sliding along the protein surface. The binding mechanism suggests that coarse-grained models are appropriate to study the motion of SSBs along ssDNA, which is expected to be central to the function carried out by the SSBs.

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Dynamics of Allosteric Transitions in Dynein

10.1101/306589 ◽

2018 ◽

Author(s):

Yonathan Goldtzvik ◽

Mauro L. Mugnai ◽

D. Thirumalai

Keyword(s):

Conformational Changes ◽

Cytoplasmic Dynein ◽

Motor Domain ◽

Coarse Grained ◽

Power Stroke ◽

Coarse Grained Model ◽

Multiple Routes ◽

Adp Release ◽

Mechanical Element ◽

Allosteric Transitions

1SummaryCytoplasmic Dynein, a motor with an unusual architecture made up of a motor domain belonging to the AAA+ family, walks on microtubule towards the minus end. Prompted by the availability of structures in different nucleotide states, we performed simulations based on a new coarse-grained model to illustrate the molecular details of the dynamics of allosteric transitions in the motor. The simulations show that binding of ATP results in the closure of the cleft between the AAA1 and AAA2, which in turn triggers conformational changes in the rest of the motor domain, thus poising dynein in the pre-power stroke state. Interactions with the microtubule, which are modeled implicitly, substantially enhances the rate of ADP release, and formation of the post-power stroke state. The dynamics associated with the key mechanical element, the linker (LN) domain, which changes from a straight to a bent state and vice versa, are highly heterogeneous suggestive of multiple routes in the pre power stroke to post power stroke transition. We show that persistent interactions between the LN and the insert loops in the AAA2 domain prevent the formation of pre-power stroke state when ATP is bound to AAA3, thus locking dynein in a non-functional repressed state. Motility in such a state may be rescued by applying mechanical force to the LN domain. Taken together, these results show how the intricate signaling dynamics within the motor domain facilitate the stepping of dynein.

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