Hierarchical coexistence of universality and diversity controls robustness and multi-functionality in intermediate filament protein networks

Proteins constitute the elementary building blocks of a vast variety of biological materials such as cellular protein networks, spider silk or bone, where they create extremely robust, multi-functional materials by self-organization of structures over many length- and time scales, from nano to macro. Some of the structural features are commonly found in a many different tissues, that is, they are highly conserved. Examples of such universal building blocks include alpha-helices, beta-sheets or tropocollagen molecules. In contrast, other features are highly specific to tissue types, such as particular filament assemblies, beta-sheet nanocrystals in spider silk or tendon fascicles. These examples illustrate that the coexistence of universality and diversity – in the following referred to as the universality-diversity paradigm (UDP) – is an overarching feature in protein materials. This paradigm is a paradox: How can a structure be universal and diverse at the same time? In protein materials, the coexistence of universality and diversity is enabled by utilizing hierarchies, which serve as an additional dimension beyond the 3D or 4D physical space. This may be crucial to understand how their structure and properties are linked, and how these materials are capable of combining seemingly disparate properties such as strength and robustness. Here we illustrate how the UDP enables to unify universal building blocks and highly diversified patterns through formation of hierarchical structures that lead to multi-functional, robust yet highly adapted structures. We illustrate these concepts in an analysis of three types of intermediate filament proteins, including vimentin, lamin and keratin

Structural hierarchies define toughness and defect-tolerance despite simple and mechanically inferior brittle building blocks

Mineralized biological materials such as bone, sea sponges or diatoms provide load-bearing and armor functions and universally feature structural hierarchies from nano to macro. Here we report a systematic investigation of the effect of hierarchical structures on toughness and defect-tolerance based on a single and mechanically inferior brittle base material, silica, using a bottom-up approach rooted in atomistic modeling. Our analysis reveals drastic changes in the material crack-propagation resistance (R-curve) solely due to the introduction of hierarchical structures that also result in a vastly increased toughness and defect-tolerance, enabling stable crack propagation over an extensive range of crack sizes. Over a range of up to four hierarchy levels, we find an exponential increase in the defect-tolerance approaching hundred micrometers without introducing additional mechanisms or materials. This presents a significant departure from the defect-tolerance of the base material, silica, which is brittle and highly sensitive even to extremely small nanometer-scale defects

Structural Rigidity of Paranemic (PX) and Juxtapose (JX) DNA Nanostructures

Crossover motifs are integral components for designing DNA based nanostructures and nanomechanical devices due to their enhanced rigidity compared to the normal B-DNA. Although the structural rigidity of the double helix B-DNA has been investigated extensively using both experimental and theoretical tools, to date there is no quantitative information about structural rigidity and the mechanical strength of parallel crossover DNA motifs. We have used fully atomistic molecular dynamics simulations in explicit solvent to get the force-extension curve of parallel DNA nanostructures to characterize their mechanical rigidity. In the presence of mono-valent Na+ ions, we find that the stretch modulus (\gamma_1) of the paranemic crossover (PX) and its topo-isomer JX DNA structure is significantly higher (~ 30%) compared to normal B-DNA of the same sequence and length. However, this is in contrast to the original expectation that these motifs are almost twice rigid compared to the double-stranded B-DNA. When the DNA motif is surrounded by a solvent with Mg2+ counterions, we find an enhanced rigidity compared to Na+ environment due to the electrostatic screening effects arising from the divalent nature of Mg2+ ions. This is the first direct determination of the mechanical strength of these crossover motifs which can be useful for the design of suitable DNA for DNA based nanostructures and nanomechanical devices with improved structural rigidity.Comment: 30 pages, 7 figure

Category Theoretic Analysis of Hierarchical Protein Materials and Social Networks

Materials in biology span all the scales from Angstroms to meters and typically consist of complex hierarchical assemblies of simple building blocks. Here we describe an application of category theory to describe structural and resulting functional properties of biological protein materials by developing so-called ologs. An olog is like a “concept web” or “semantic network” except that it follows a rigorous mathematical formulation based on category theory. This key difference ensures that an olog is unambiguous, highly adaptable to evolution and change, and suitable for sharing concepts with other olog. We consider simple cases of beta-helical and amyloid-like protein filaments subjected to axial extension and develop an olog representation of their structural and resulting mechanical properties. We also construct a representation of a social network in which people send text-messages to their nearest neighbors and act as a team to perform a task. We show that the olog for the protein and the olog for the social network feature identical category-theoretic representations, and we proceed to precisely explicate the analogy or isomorphism between them. The examples presented here demonstrate that the intrinsic nature of a complex system, which in particular includes a precise relationship between structure and function at different hierarchical levels, can be effectively represented by an olog. This, in turn, allows for comparative studies between disparate materials or fields of application, and results in novel approaches to derive functionality in the design of de novo hierarchical systems. We discuss opportunities and challenges associated with the description of complex biological materials by using ologs as a powerful tool for analysis and design in the context of materiomics, and we present the potential impact of this approach for engineering, life sciences, and medicine.Presidential Early Career Award for Scientists and Engineers (N000141010562)United States. Army Research Office. Multidisciplinary University Research Initiative (W911NF0910541)United States. Office of Naval Research (grant N000141010841)Massachusetts Institute of Technology. Dept. of MathematicsStudienstiftung des deutschen VolkesClark BarwickJacob Luri

Strength of Hydrogen Bond Network Takes Crucial Roles in the Dissociation Process of Inhibitors from the HIV-1 Protease Binding Pocket

To understand the underlying mechanisms of significant differences in dissociation rate constant among different inhibitors for HIV-1 protease, we performed steered molecular dynamics (SMD) simulations to analyze the entire dissociation processes of inhibitors from the binding pocket of protease at atomistic details. We found that the strength of hydrogen bond network between inhibitor and the protease takes crucial roles in the dissociation process. We showed that the hydrogen bond network in the cyclic urea inhibitors AHA001/XK263 is less stable than that of the approved inhibitor ABT538 because of their large differences in the structures of the networks. In the cyclic urea inhibitor bound complex, the hydrogen bonds often distribute at the flap tips and the active site. In contrast, there are additional accessorial hydrogen bonds formed at the lateral sides of the flaps and the active site in the ABT538 bound complex, which take crucial roles in stabilizing the hydrogen bond network. In addition, the water molecule W301 also plays important roles in stabilizing the hydrogen bond network through its flexible movement by acting as a collision buffer and helping the rebinding of hydrogen bonds at the flap tips. Because of its high stability, the hydrogen bond network of ABT538 complex can work together with the hydrophobic clusters to resist the dissociation, resulting in much lower dissociation rate constant than those of cyclic urea inhibitor complexes. This study may provide useful guidelines for design of novel potent inhibitors with optimized interactions