Simulation of biomolecular interactions with inorganic and organic surfaces as a challenge for future nanotechnologies
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Interfacing biomolecules with conventional materials of technological interest is a formidable challenge as well as a prerequisite to propose alternative and innovative routes in micro and nanotechnologies at large.
Nature provides extraordinary capacity of generating a wide range of sophisticated functions thanks to complex networks of intermolecular interactions that have been optimized over millions of years of natural evolution. This idea is in accordance with the general goals of nanosciences to downscale and express functions . In turn, mimicking and diverting these complex biomolecular pathways in non-biological environment raises new burning questions that need to be solved to target biological processes but also to renew our technologies for non-biological applications.
Several key examples have marked the last decade at the crossroads of biology, physics and chemistry to offer new perspectives for technologists. The most illustrative one, so-called DNA nanotechnologies, is relying on our fundamental understanding of DNA polymer and our capability of synthetizing DNA strands of multiple natures, chemically or biochemically modified, to be turned into technological material. In doing so, DNA can been used to organize inorganic matter in a hierarchical and programmable manner, to achieve nanoenergetic (Al/CuO) materials, to organize supercrystals of nanoparticles with programmable structures and lattice parameters. Self-organization of DNA templates (origami, Seeman tiles) can be used to dictate the precise positioning and connection of materials and molecules in any deliberately designed structure. On the other hand, DNA or RNA aptamers have demonstrated unprecedented capacity to selectively target a wide range of molecules, biological or not, for sensor applications. Along the same line, proteins offer similar promising possibilities in which phage and cell display can be used to design new peptide sequences with dedicated functionality, binding organic to inorganic materials. Other examples of nano-objects, viruses, capsids, cells, membranes… can be assimilated as self-assembled nanomaterial of well-defined size and shape, authorizing cutting-edge technological perspectives.
Playing with bio and non-bio materials, i.e. coupling biological and non-biological interactions, offers the most complex technological challenge ever. Facing this challenge requires powerful predictive modeling to avoid inextricable trials and errors experimental procedures. Computational studies are expected to play a crucial role to fundamentally depict the complexity emanating from bio-hybrid materials and devices, and to assist experimental effort towards the development of new multifunctional materials and related innovative nanosystems. Main research needs focus on bio/non bio interactions, multi-scale nano-objects and assemblies for bio-hybrid technologies. As the community of experimentalists is now well identified and organized, much effort is still to be done on the theoretical side where tremendous methodological challenges are to be overcome. We expect a CECAM workshop to provide one of the best existing frameworks to launch and organize this emerging research domain at the European level and the associated researcher community. This will be done in collaboration with the existing COST network “bio-inspired technologies: from concept to application”, in which a report of deliverables on this topic is programmed and could be discussed within this workshop. Also, one or two keynote speakers will be devoted to an experimental and technological overview of bio-hybrid technologies (for instance on both protein and DNA-based materials and technologies).
In the last years, many bio-hybrid systems have emerged offering the possibility of overcoming major technological limitations. In this part, we shortly summarize a current state of the art of bio-hybrid technologies through selected achievements that integrate naturally optimized biological components. The main technological applications cover a wide range of domains, ranging from microscopic to macroscopic scales, among which we can cite sensors, activators, transport, energy storage and supply, functional bio-mimetic material for medical implants…
DNA is considered today as the most promising materials for nanobiotechnologies and a growing number of European groups are involved in its use. Since the seminal work of N.E. Seeman, DNA as a material for nanotechnology is widely used to connect or functionalize different nanostructures and to obtain versatile 2D and 3D shapes [2-4]. As pioneered by Rothemund [5-6], the use of a viral DNA scaffold to build DNA origami has further boosted the development of DNA nanotechnology, expanding the scale of addressable nanostructures. As a consequence, DNA origami can also be used as an information-bearing seed for nucleating algorithm . Origami scaffolds, as seed self-supporting information, then control the growth of a computed structure and prevent from nucleation process competition. This approach, by controlling the competition between nucleation and growth process, allows reducing errors that can be introduced by self-assembly of defined structure geometry. On the applicative side, programmed origami-based DNA can be used to organize ordered systems of nano-objects like nanoparticles or nanotubes [8,9]. Along the same line, viruses can be considered as self-assembled materials with controlled arrangement at the molecular scale. They can consequently provide, through genetic engineering, new functionalized arrangement of systems and devices. A known result is the genetically engineered M13 virus that serves as a model system and is used as a programmable molecular building block to template inorganic materials growth .
Recently, amazing progresses in the control of complex structures has even led to the conception of DNA walking devices able to combine numbers of functions to achieve the signal transduction or the molecular transport for example [11,12]. Other RNA or protein-based nanomachines have also been engineered to integrate a wide range of active functions into nanodevices, like walkers moving onto inorganic surfaces .
Biomolecules unique 3D folding properties also open new routes for molecular recognition and sensor applications. Many groups have developed high-throughput protocols for the selection of biomolecules, e.g. aptamers fabricated with the SELEX process or peptide sequences with phage and cell display methods, optimized for chemical or biological applications . Aptamers and peptides with specific sequences are also used to target and self-assemble inorganic nanoparticles for numerous applications, as for instance, the fabrication of Janus (two-faced) nanoparticles for biosensors and nano-vectors applications . Another example is the design of synthetic peptide sequence with dedicated functionalities (energy storage, enzymatic activity, transport, assembly), able to bind organic or inorganic specific partners [16-17].
As we previously said, bio-inspired fabrication methods provide the unprecedented capability to build elaborate and complex architectures and functions. This strategy also shows capability to control the growth and hierarchical organization of inorganic minerals along with organic materials. This so-called biomineralization processes, based on the use of specific proteins, can readily design biosensors, plasmonic and nanoelectronic networks or electroactive materials . Bio-inspired materials provide new routes to design new materials of various shapes and compositions, to engineer interface properties using genetic engineering, biological combinatorial methods or targeted chemical synthesis thus increasing the efficiency of inorganic nano objects. Another important route that should lead to significant improvement on the design of new materials and functions is the development of a new class of bio-inspired nano-micro-systems that lead to new conceptions of logical functions and dynamic patterning with error corrections.
Other remarkable achievements that we can cite combine Top-Down and Bottom-Up approaches. For instance, micro contact printing technology and Bio-Inspired fabrication methods have been used to assemble nanowires, to fabricate microbattery electrodes with virus or to design arrays of micro reactors to investigate bio-molecular motor activity. Several works have notably reported elaborate strategies that create ordered DNA origami arrays attached to patterned Au or Si substrate, combining for instance conventional e-beam lithography, lift-off process, and incubation steps in a solution containing thiolated DNA strands extended of DNA origami nanotubes .
Thanks to prodigious progresses in this field, coupled with mature bottom up fabrication methods, it is now possible to imagine an almost infinite variety of bio-hybrid materials and functions. However, despite the related stakes, theoretical modeling for bio-hybrid materials and their technological applications is scarce. To deal with biomolecular interaction, well-established multi-scale strategies are limited and not fully representative, and must be extended to new levels of modeling. Multi-model competencies are needed to address the complexity and variety of nano to meso bio-hybrid architectures involving polymers, biomolecules, inorganic materials and their interfaces . Since the seminal work by Braun et al.  who simulated peptide binding on gold surface with classical MD, many theoretical studies have been published, investigating the dynamics, thermodynamics, and mechanical properties of bionanosystems. Using the most accurate already available methods (mainly QM and MD), they are only feasible for case studies and need enormous computer power [22,23]. When precision of the classical mechanics is not satisfactory, laws of quantum mechanics can be used, though these laws require more extensive calculations. Oppositely, for larger molecular systems, some more simplified description can be used. Thus, the most efficient methods for nanostructures and biomolecules are different, which makes biohybrid simulation even more challenging. In particular, the interaction of nanoparticles with functional binding sites of biomolecules is recurrent in the literature, and so is the adsorption of protein or DNA on a surface [24-28]. The latter has resulted in the developments of new force fields to characterize specific protein-surface interactions [30-33] limited to two usual surfaces (Au and Si). The investigation of adhesion phenomena at the solid-liquid interface, taking into account the molecular nature of the solvent and considering a realistic model for the surface is a related issue. It often uses continuum theories, such as DLVO, to treat nonspecific interactions (van der Waals, etc) and longer-range electrostatic forces between charged surfaces . In the spectra of existing modelling tools that have been tested, we can also cite QM and QM/MM approaches [35-37], Monte Carlo methods [38-39] or mesoscale models . However, general strategies are not yet available. They remain a challenge and require special efforts to propose viable multi-model strategies that extend the capabilities of conventional methods taken separately [40-42].
Interestingly, the modeling of biomolecular interactions in itself has for long been the source of intense studies. Computational biology is of crucial importance to unravel mechanisms of complex molecules like DNA, proteins, and of their interactions for drug design purpose. A range of methods such as Monte Carlo, Normal Modes, Static Modes and of course Molecular Dynamics associated with very specific interatomic potentials have been developed . They have demonstrated to be efficient for a range of questions and are still under great debate within the scope of biology uniquely. The connection with these domains, the linking of methodologies and tools already developed in this frame will be questioned in the present workshop.
Marie Brut (LAAS-CNRS) - Organiser
Alain Esteve (LAAS-CNRS) - Organiser
Aleman Carlos (Universitat Politecnica de Catalunya) - Organiser
Vashishta Priya (University of Southern California) - Organiser