Life | Special Issue : Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells

Research

14 pages, 43197 KiB

Open AccessCommunication

Molecular Dynamics Simulation of the Complex of PDE5 and Evodiamine

by Ayame Kobayashi, Motokuni Nakajima, Yoh Noguchi, Ryota Morikawa, Yukiko Matsuo and Masako Takasu

Life 2023, 13(2), 578; https://doi.org/10.3390/life13020578 - 18 Feb 2023

Cited by 3 | Viewed by 2233

Abstract

Alzheimer’s disease is an irreversible neurological disorder for which there are no effective small molecule therapeutics. A phosphodiesterase 5 (PDE5) inhibitor is a candidate medicine for the treatment of Alzheimer’s disease. Rutaecarpine, an indole alkaloid found in Euodiae Fructus, has inhibitory activity [...] Read more.

Alzheimer’s disease is an irreversible neurological disorder for which there are no effective small molecule therapeutics. A phosphodiesterase 5 (PDE5) inhibitor is a candidate medicine for the treatment of Alzheimer’s disease. Rutaecarpine, an indole alkaloid found in Euodiae Fructus, has inhibitory activity for PDE5. Euodiae Fructus contains more evodiamine than rutaecarpine. Therefore, we performed molecular dynamics simulations of the complex of PDE5 and evodiamine. The results showed that the PDE5 and (−)-evodiamine complexes were placed inside the reaction center compared to the case of PDE5 and (+)-evodiamine complex. The binding of (−)-evodiamine to PDE5 increased the root-mean-square deviation and radius of gyration of PDE5. In the PDE5 with (−)-evodiamine complex, the value of the root-mean-square fluctuation of the M-loop, which is thought to be important for activity, increased. This result suggests that (−)-evodiamine may have inhibitory activity. Full article

(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)

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20 pages, 62596 KiB

Open AccessArticle

Dissipative Particle Dynamics Simulations for Shape Change of Growing Lipid Bilayer Vesicles

by Hiromi Mitsuhashi, Ryota Morikawa, Yoh Noguchi and Masako Takasu

Life 2023, 13(2), 306; https://doi.org/10.3390/life13020306 - 22 Jan 2023

Cited by 2 | Viewed by 2058

Abstract

The characteristic shape changes observed in the growth and division of L-form cells have been explained by several theoretical studies and simulations using a vesicle model in which the membrane area increases with time. In those theoretical studies, characteristic shapes such as tubulation [...] Read more.

The characteristic shape changes observed in the growth and division of L-form cells have been explained by several theoretical studies and simulations using a vesicle model in which the membrane area increases with time. In those theoretical studies, characteristic shapes such as tubulation and budding were reproduced in a non-equilibrium state, but it was not possible to incorporate deformations that would change the topology of the membrane. We constructed a vesicle model in which the area of the membrane increases using coarse-grained particles and analyzed the changes in the shape of growing membrane by the dissipative particle dynamics (DPD) method. In the simulation, lipid molecules were added to the lipid membrane at regular time intervals to increase the surface area of the lipid membrane. As a result, it was found that the vesicle deformed into a tubular shape or a budding shape depending on the conditions for adding lipid molecules. This suggests that the difference in the place where new lipid molecules are incorporated into the cell membrane during the growth of L-form cells causes the difference in the transformation pathway of L-form cells. Full article

(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)

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11 pages, 3079 KiB

Open AccessArticle

Redshifting and Blueshifting of β82 Chromophores in the Phycocyanin Hexamer of Porphyridium purpureum Phycobilisomes Due to Linker Proteins

by Hiroto Kikuchi

Life 2022, 12(11), 1833; https://doi.org/10.3390/life12111833 - 9 Nov 2022

Cited by 2 | Viewed by 2206

Abstract

Phycobilisomes in cyanobacteria and red algae are large protein complexes that absorb light and transfer energy for use in photosynthesis. The light energy absorbed by chromophores binding to phycobiliproteins in the peripheral rods can be funneled to the core through chromophores at very [...] Read more.

Phycobilisomes in cyanobacteria and red algae are large protein complexes that absorb light and transfer energy for use in photosynthesis. The light energy absorbed by chromophores binding to phycobiliproteins in the peripheral rods can be funneled to the core through chromophores at very high efficiency. The molecular mechanism of excitation energy transfer within a phycobilisome is an example of a higher and unique function in a living organism. However, the mechanism underlying the high efficiency remains unclear. Thus, this study was carried out as a step to resolve this mechanism theoretically. The three-dimensional structure of phycobilisomes containing the linker proteins of the red alga Porphyridium purpureum was determined by cryoelectron microscopy at 2.82 Å resolution in 2020. Using these data, the absorption wavelength of each β82 chromophore in the phycocyanin hexamer located next to the core was calculated using quantum chemical treatment, considering the electric effect from its surrounding phycocyanin proteins and two linker proteins. In addition to unaffected chromophores, chromophores that were redshifted and blueshifted under the electrical influence of the two linker proteins were found. Namely, the chromophore serving as the energy sink in the rod was determined. Full article

(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)

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12 pages, 576 KiB

Open AccessArticle

Non-Markov-Type Analysis and Diffusion Map Analysis for Molecular Dynamics Trajectory of Chignolin at a High Temperature

by Hiroshi Fujisaki, Hiromichi Suetani, Luca Maragliano and Ayori Mitsutake

Life 2022, 12(8), 1188; https://doi.org/10.3390/life12081188 - 3 Aug 2022

Cited by 2 | Viewed by 2473

Abstract

We apply the non-Markov-type analysis of state-to-state transitions to nearly microsecond molecular dynamics (MD) simulation data at a folding temperature of a small artificial protein, chignolin, and we found that the time scales obtained are consistent with our previous result using the weighted [...] Read more.

We apply the non-Markov-type analysis of state-to-state transitions to nearly microsecond molecular dynamics (MD) simulation data at a folding temperature of a small artificial protein, chignolin, and we found that the time scales obtained are consistent with our previous result using the weighted ensemble simulations, which is a general path-sampling method to extract the kinetic properties of molecules. Previously, we also applied diffusion map (DM) analysis, which is one of a manifold of learning techniques, to the same trajectory of chignolin in order to cluster the conformational states and found that DM and relaxation mode analysis give similar results for the eigenvectors. In this paper, we divide the same trajectory into shorter pieces and further apply DM to such short-length trajectories to investigate how the obtained eigenvectors are useful to characterize the conformational change of chignolin. Full article

(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)

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13 pages, 2185 KiB

Open AccessArticle

Free-Energy Profile Analysis of the Catalytic Reaction of Glycinamide Ribonucleotide Synthetase

by Norifumi Yamamoto, Genichi Sampei and Gota Kawai

Life 2022, 12(2), 281; https://doi.org/10.3390/life12020281 - 14 Feb 2022

Cited by 4 | Viewed by 2995

Abstract

The second step in the de novo biosynthetic pathway of purine is catalyzed by PurD, which consumes an ATP molecule to produce glycinamide ribonucleotide (GAR) from glycine and phosphoribosylamine (PRA). PurD initially reacts with ATP to produce an intermediate, glycyl-phosphate, which then reacts [...] Read more.

The second step in the de novo biosynthetic pathway of purine is catalyzed by PurD, which consumes an ATP molecule to produce glycinamide ribonucleotide (GAR) from glycine and phosphoribosylamine (PRA). PurD initially reacts with ATP to produce an intermediate, glycyl-phosphate, which then reacts with PRA to produce GAR. The structure of the glycyl-phosphate intermediate bound to PurD has not been determined. Therefore, the detailed reaction mechanism at the molecular level is unclear. Here, we developed a computational protocol to analyze the free-energy profile for the glycine phosphorylation process catalyzed by PurD, which examines the free-energy change along a minimum energy path based on a perturbation method combined with the quantum mechanics and molecular mechanics hybrid model. Further analysis revealed that during the formation of glycyl-phosphate, the partial atomic charge distribution within the substrate molecules was not localized according to the formal charges, but was delocalized overall, which contributed significantly to the interaction with the charged amino acid residues in the ATP-grasp domain of PurD. Full article

(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)

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15 pages, 2483 KiB

Open AccessArticle

Analysis of Fluctuation in the Heme-Binding Pocket and Heme Distortion in Hemoglobin and Myoglobin

by Hiroko X. Kondo and Yu Takano

Life 2022, 12(2), 210; https://doi.org/10.3390/life12020210 - 29 Jan 2022

Cited by 9 | Viewed by 4187

Abstract

Heme is located in the active site of proteins and has diverse and important biological functions, such as electron transfer and oxygen transport and/or storage. The distortion of heme porphyrin is considered an important factor for the diverse functions of heme because it [...] Read more.

Heme is located in the active site of proteins and has diverse and important biological functions, such as electron transfer and oxygen transport and/or storage. The distortion of heme porphyrin is considered an important factor for the diverse functions of heme because it correlates with the physical properties of heme, such as oxygen affinity and redox potential. Therefore, clarification of the relationship between heme distortion and the protein environment is crucial in protein science. Here, we analyzed the fluctuation in heme distortion in the protein environment for hemoglobin and myoglobin using molecular dynamics (MD) simulations and quantum mechanical (QM) calculations as well as statistical analysis of the protein structures of hemoglobin and myoglobin stored in Protein Data Bank. Our computation and statistical analysis showed that the protein environment for hemoglobin and myoglobin prominently affects the doming distortion of heme porphyrin, which correlates with its oxygen affinity, and that the magnitude of distortion is different between hemoglobin and myoglobin. These results suggest that heme distortion is affected by its protein environment and fluctuates around its fitted conformation, leading to physical properties that are appropriate for protein functions. Full article

(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)

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13 pages, 3756 KiB

Open AccessArticle

Enhanced Conformational Sampling of Nanobody CDR H3 Loop by Generalized Replica-Exchange with Solute Tempering

by Ren Higashida and Yasuhiro Matsunaga

Life 2021, 11(12), 1428; https://doi.org/10.3390/life11121428 - 18 Dec 2021

Cited by 4 | Viewed by 3384

Abstract

The variable domains of heavy-chain antibodies, known as nanobodies, are potential substitutes for IgG antibodies. They have similar affinities to antigens as antibodies, but are more heat resistant. Their small size allows us to exploit computational approaches for structural modeling or design. Here, [...] Read more.

The variable domains of heavy-chain antibodies, known as nanobodies, are potential substitutes for IgG antibodies. They have similar affinities to antigens as antibodies, but are more heat resistant. Their small size allows us to exploit computational approaches for structural modeling or design. Here, we investigate the applicability of an enhanced sampling method, a generalized replica-exchange with solute tempering (gREST) for sampling CDR-H3 loop structures of nanobodies. In the conventional replica-exchange methods, temperatures of only a whole system or scaling parameters of a solute molecule are selected for temperature or parameter exchange. In gREST, we can flexibly select a part of a solute molecule and a part of the potential energy terms as a parameter exchange region. We selected the CDR-H3 loop and investigated which potential energy term should be selected for the efficient sampling of the loop structures. We found that the gREST with dihedral terms can explore a global conformational space, but the relaxation to the global equilibrium is slow. On the other hand, gREST with all the potential energy terms can sample the equilibrium distribution, but the structural exploration is slower than with dihedral terms. The lessons learned from this study can be applied to future studies of loop modeling. Full article

(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)

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13 pages, 2491 KiB

Open AccessArticle

A Free-Energy Landscape Analysis of Calmodulin Obtained from an NMR Data-Utilized Multi-Scale Divide-and-Conquer Molecular Dynamics Simulation

by Hiromitsu Shimoyama and Yasuteru Shigeta

Life 2021, 11(11), 1241; https://doi.org/10.3390/life11111241 - 16 Nov 2021

Cited by 1 | Viewed by 2359

Abstract

Calmodulin (CaM) is a multifunctional calcium-binding protein, which regulates a variety of biochemical processes. CaM acts through its conformational changes and complex formation with its target enzymes. CaM consists of two globular domains (N-lobe and C-lobe) linked by an extended linker region. Upon [...] Read more.

Calmodulin (CaM) is a multifunctional calcium-binding protein, which regulates a variety of biochemical processes. CaM acts through its conformational changes and complex formation with its target enzymes. CaM consists of two globular domains (N-lobe and C-lobe) linked by an extended linker region. Upon calcium binding, the N-lobe and C-lobe undergo local conformational changes, followed by a major conformational change of the entire CaM to wrap the target enzyme. However, the regulation mechanisms, such as allosteric interactions, which regulate the large structural changes, are still unclear. In order to investigate the series of structural changes, the free-energy landscape of CaM was obtained by multi-scale divide-and-conquer molecular dynamics (MSDC-MD). The resultant free-energy landscape (FEL) shows that the Ca²⁺ bound CaM (holo-CaM) would take an experimentally famous elongated structure, which can be formed in the early stage of structural change, by breaking the inter-domain interactions. The FEL also shows that important interactions complete the structural change from the elongated structure to the ring-like structure. In addition, the FEL might give a guiding principle to predict mutational sites in CaM. In this study, it was demonstrated that the movement process of macroscopic variables on the FEL may be diffusive to some extent, and then, the MSDC-MD is suitable to the parallel computation. Full article

(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)

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12 pages, 3923 KiB

Open AccessArticle

Multiscale Enhanced Sampling Using Machine Learning

by Kei Moritsugu

Life 2021, 11(10), 1076; https://doi.org/10.3390/life11101076 - 12 Oct 2021

Cited by 8 | Viewed by 2782

Abstract

Multiscale enhanced sampling (MSES) allows for an enhanced sampling of all-atom protein structures by coupling with the accelerated dynamics of the associated coarse-grained (CG) model. In this paper, we propose an MSES extension to replace the CG model with the dynamics on the [...] Read more.

Multiscale enhanced sampling (MSES) allows for an enhanced sampling of all-atom protein structures by coupling with the accelerated dynamics of the associated coarse-grained (CG) model. In this paper, we propose an MSES extension to replace the CG model with the dynamics on the reduced subspace generated by a machine learning approach, the variational autoencoder (VAE). The molecular dynamic (MD) trajectories of the ribose-binding protein (RBP) in both the closed and open forms were used as the input by extracting the inter-residue distances as the structural features in order to train the VAE model, allowing the encoded latent layer to characterize the difference in the structural dynamics of the closed and open forms. The interpolated data characterizing the RBP structural change in between the closed and open forms were thus efficiently generated in the low-dimensional latent space of the VAE, which was then decoded into the time-series data of the inter-residue distances and was useful for driving the structural sampling at an atomistic resolution via the MSES scheme. The free energy surfaces on the latent space demonstrated the refinement of the generated data that had a single basin into the simulated data containing two closed and open basins, thus illustrating the usefulness of the MD simulation together with the molecular mechanics force field in recovering the correct structural ensemble. Full article

(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)

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