The coarse-grained Martini force field is widely used in biomolecular simulations. Here we present the refined model, Martini 3 ( http://cgmartini.nl ), with an improved interaction balance, new bead ...types and expanded ability to include specific interactions representing, for example, hydrogen bonding and electronic polarizability. The updated model allows more accurate predictions of molecular packing and interactions in general, which is exemplified with a vast and diverse set of applications, ranging from oil/water partitioning and miscibility data to complex molecular systems, involving protein-protein and protein-lipid interactions and material science applications as ionic liquids and aedamers.
Abstract
The detailed understanding of the binding of small molecules to proteins is the key for the development of novel drugs or to increase the acceptance of substrates by enzymes. Nowadays, ...computer-aided design of protein–ligand binding is an important tool to accomplish this task. Current approaches typically rely on high-throughput docking essays or computationally expensive atomistic molecular dynamics simulations. Here, we present an approach to use the recently re-parametrized coarse-grained Martini model to perform unbiased millisecond sampling of protein–ligand interactions of small drug-like molecules. Remarkably, we achieve high accuracy without the need of any a priori knowledge of binding pockets or pathways. Our approach is applied to a range of systems from the well-characterized T4 lysozyme over members of the GPCR family and nuclear receptors to a variety of enzymes. The presented results open the way to high-throughput screening of ligand libraries or protein mutations using the coarse-grained Martini model.
Photosynthesis is regulated by a dynamic interplay between proteins, enzymes, pigments, lipids, and cofactors that takes place on a large spatio-temporal scale. Molecular dynamics (MD) simulations ...provide a powerful toolkit to investigate dynamical processes in (bio)molecular ensembles from the (sub)picosecond to the (sub)millisecond regime and from the Å to hundreds of nm length scale. Therefore, MD is well suited to address a variety of questions arising in the field of photosynthesis research. In this review, we provide an introduction to the basic concepts of MD simulations, at atomistic and coarse-grained level of resolution. Furthermore, we discuss applications of MD simulations to model photosynthetic systems of different sizes and complexity and their connection to experimental observables. Finally, we provide a brief glance on which methods provide opportunities to capture phenomena beyond the applicability of classical MD.
Plant light-harvesting complex II (LHCII) is the key antenna complex for plant photosynthesis. We present coarse-grained molecular dynamics simulations of monomeric and trimeric LHCII in a realistic ...thylakoid membrane environment based on the Martini force field. The coarse-grained protein model has been optimized with respect to atomistic reference simulations. Our simulations provide detailed insights in the thylakoid lipid fingerprint of LHCII which compares well with experimental data from membrane protein purification. Comparing the monomer and trimeric LHCII reveals a stabilizing effect of trimerization on the chromophores as well as the protein. Moreover, the average chromophore distance shortens in the trimer leading to stronger excitonic couplings. When changing the native thylakoid environment to a model membrane the protein flexibility remains constant, whereas the chromophore flexibility is reduced. Overall, the presented LHCII model lays the foundation to investigate the μs dynamics of this key antenna protein of plants.
Several different mutations of the protein copper, zinc superoxide dismutase (SOD1) produce the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The molecular mechanism by which the ...diverse mutations converge to a similar pathology is currently unknown. The electrostatic loop (EL) of SOD1 is known to be affected in all of the studied ALS-linked mutations of SOD1. In this work, we employ a multiscale simulation approach to show that this perturbation corresponds to an increased probability of the EL detaching from its native position, exposing the metal site of the protein to water. From extensive atomistic and coarse-grained molecular dynamics (MD) simulations, we identify an allosteric pathway that explains the action of the distant G93A mutation on the EL. Finally, we employ quantum mechanics/molecular mechanics MD simulations to show that the opening of the EL decreases the Zn(II) affinity of the protein. As the loss of Zn(II) is at the center of several proposed pathogenic mechanisms in SOD1-linked ALS, the structural effect identified here not only is in agreement with the experimental data but also places the opening of the electrostatic loop as the possible main pathogenic effect for a significant number of ALS-linked SOD1 mutations.
Photopharmacology uses light to regulate the biological activity of drugs. This precise control is obtained through the incorporation of molecular photoswitches into bioactive molecules. A major ...challenge for photopharmacology is the rational design of photoswitchable drugs that show light-induced activation. Computer-aided drug design is an attractive approach toward more effective, targeted design. Herein, we critically evaluated different structure-based approaches for photopharmacology with Escherichia coli dihydrofolate reductase (eDHFR) as a case study. Through the iterative examination of our hypotheses, we progressively tuned the design of azobenzene-based, photoswitchable eDHFR inhibitors in five design–make–switch–test–analyze cycles. Targeting a hydrophobic subpocket of the enzyme and a specific salt bridge only with the thermally metastable cis-isomer emerged as the most promising design strategy. We identified three inhibitors that could be activated upon irradiation and reached potencies in the low-nanomolar range. Above all, this systematic study provided valuable insights for future endeavors toward rational photopharmacology.
Perspective: a stirring role for metabolism in cells Losa, José; Leupold, Simeon; Alonso‐Martinez, Diego ...
Molecular systems biology,
April 2022, 2022-04-00, 20220401, 2022-04-01, Letnik:
18, Številka:
4
Journal Article
Recenzirano
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Based on recent findings indicating that metabolism might be governed by a limit on the rate at which cells can dissipate Gibbs energy, in this Perspective, we propose a new mechanism of how ...metabolic activity could globally regulate biomolecular processes in a cell. Specifically, we postulate that Gibbs energy released in metabolic reactions is used to perform work, allowing enzymes to self‐propel or to break free from supramolecular structures. This catalysis‐induced enzyme movement will result in increased intracellular motion, which in turn can compromise biomolecular functions. Once the increased intracellular motion has a detrimental effect on regulatory mechanisms, this will establish a feedback mechanism on metabolic activity, and result in the observed thermodynamic limit. While this proposed explanation for the identified upper rate limit on cellular Gibbs energy dissipation rate awaits experimental validation, it offers an intriguing perspective of how metabolic activity can globally affect biomolecular functions and will hopefully spark new research.
Recent findings suggested that metabolism is governed by a limit on the rate at which cells can dissipate Gibbs energy. This Perspective proposes a new mechanism of how metabolic activity and the Gibbs energy released in metabolic reactions could globally regulate biomolecular processes.
Biaryl sulfonamides are excellent candidates for the azologization approach that yields photoswitchable drugs more active in their metastable cis state, compared to the stable trans state. Here we ...present the scope and limitations of this strategy for rational design in photopharmacology.
Optimal control theory and optimal control experiments are state-of-the-art tools to control quantum systems. Both methods have been demonstrated successfully for numerous applications in molecular ...physics, chemistry and biology. Modulated light pulses could be realized, driving these various control processes. Next to the control efficiency, a key issue is the understanding of the control mechanism. An obvious way is to seek support from theory. However, the underlying search strategies in theory and experiment towards the optimal laser field differ. While the optimal control theory operates in the time domain, optimal control experiments optimize the laser fields in the frequency domain. This also implies that both search procedures experience a different bias and follow different pathways on the search landscape. In this perspective we review our recent developments in optimal control theory and their applications. Especially, we focus on approaches, which close the gap between theory and experiment. To this extent we followed two ways. One uses sophisticated optimization algorithms, which enhance the capabilities of optimal control experiments. The other is to extend and modify the optimal control theory formalism in order to mimic the experimental conditions.
Optimal control theory and experiments are contemporary tools. We discuss possible routes to interconnect both search spaces for optimal synergy.
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