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3 pages, 191 KiB

Open AccessEditorial

Molecular Dynamics Simulations: Advances and Applications

by Hugo A. L. Filipe and Luís M. S. Loura

Molecules 2022, 27(7), 2105; https://doi.org/10.3390/molecules27072105 - 24 Mar 2022

Cited by 73 | Viewed by 9264

Abstract

Molecular dynamics (MD) simulations have led to great advances in many scientific disciplines, such as chemical physics, materials science, and biophysics [...] Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations: Advances and Applications)

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19 pages, 2420 KiB

Open AccessArticle

Interactions between Rhodamine Dyes and Model Membrane Systems—Insights from Molecular Dynamics Simulations

by Nisa Magalhães, Guilherme M. Simões, Cristiana Ramos, Jaime Samelo, Alexandre C. Oliveira, Hugo A. L. Filipe, João P. Prates Ramalho, Maria João Moreno and Luís M. S. Loura

Molecules 2022, 27(4), 1420; https://doi.org/10.3390/molecules27041420 - 19 Feb 2022

Cited by 12 | Viewed by 4460

Abstract

Background: rhodamines are dyes widely used as fluorescent tags in cell imaging, probing of mitochondrial membrane potential, and as P-glycoprotein model substrates. In all these applications, detailed understanding of the interaction between rhodamines and biomembranes is fundamental. Methods: we combined atomistic molecular dynamics [...] Read more.

Background: rhodamines are dyes widely used as fluorescent tags in cell imaging, probing of mitochondrial membrane potential, and as P-glycoprotein model substrates. In all these applications, detailed understanding of the interaction between rhodamines and biomembranes is fundamental. Methods: we combined atomistic molecular dynamics (MD) simulations and fluorescence spectroscopy to characterize the interaction between rhodamines 123 and B (Rh123 and RhB, respectively) and POPC bilayers. Results: while the xanthene moiety orients roughly parallel to the membrane plane in unrestrained MD simulations, variations on the relative position of the benzoic ring (below the xanthene for Rh123, above it for RhB) were observed, and related to the structure of the two dyes and their interactions with water and lipids. Subtle distinctions were found among different ionization forms of the probes. Experimentally, RhB displayed a lipid/water partition coefficient more than two orders of magnitude higher than Rh123, in agreement with free energy profiles obtained from umbrella sampling MD. Conclusions: this work provided detailed insights on the similarities and differences in the behavior of bilayer-inserted Rh123 and RhB, related to the structure of the probes. The much higher affinity of RhB for the membranes increases the local concentration and explains its higher apparent affinity for P-glycoprotein reconstituted in model membranes. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations: Advances and Applications)

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17 pages, 6023 KiB

Open AccessEditor’s ChoiceArticle

Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations

by Shihao Yao, Boyuan Ma, Qiuzi Yi, Min-Xin Guan and Xiaohui Cang

Molecules 2022, 27(3), 1071; https://doi.org/10.3390/molecules27031071 - 5 Feb 2022

Cited by 6 | Viewed by 2669

Abstract

The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge [...] Read more.

The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge on these networks is still limited. In the current work, we focus on more conserved m-gate network in the c-state AAC. All-atom molecular dynamics (MD) simulations on a variety of mutants and the CATR-AAC complex have revealed that: (1) without involvement of other positive residues, the charged residues from the three Px[DE]xx[KR] motifs only are prone to form symmetrical inter-helical network; (2) R235 plays a determinant role for the asymmetry in m-gate network of AAC; (3) R235 significantly strengthens the interactions between H3 and H5; (4) R79 exhibits more significant impact on m-gate than R279; (5) CATR promotes symmetry in m-gate mainly through separating R234 from D231 and fixing R79; (6) vulnerability of the H2-H3 interface near matrix side could be functionally important. Our results provide new insights into the highly conserved yet variable m-gate network in the big mitochondrial carrier family. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations: Advances and Applications)

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14 pages, 1096 KiB

Open AccessArticle

Comparing Dimerization Free Energies and Binding Modes of Small Aromatic Molecules with Different Force Fields

by Ilias Patmanidis, Riccardo Alessandri, Alex H. de Vries and Siewert J. Marrink

Molecules 2021, 26(19), 6069; https://doi.org/10.3390/molecules26196069 - 7 Oct 2021

Cited by 3 | Viewed by 2698

Abstract

Dimerization free energies are fundamental quantities that describe the strength of interaction of different molecules. Obtaining accurate experimental values for small molecules and disentangling the conformations that contribute most to the binding can be extremely difficult, due to the size of the systems [...] Read more.

Dimerization free energies are fundamental quantities that describe the strength of interaction of different molecules. Obtaining accurate experimental values for small molecules and disentangling the conformations that contribute most to the binding can be extremely difficult, due to the size of the systems and the small energy differences. In many cases, one has to resort to computational methods to calculate such properties. In this work, we used molecular dynamics simulations in conjunction with metadynamics to calculate the free energy of dimerization of small aromatic rings, and compared three models from popular online servers for atomistic force fields, namely G54a7, CHARMM36 and OPLS. We show that, regardless of the force field, the profiles for the dimerization free energy of these compounds are very similar. However, significant care needs to be taken when studying larger molecules, since the deviations from the trends increase with the size of the molecules, resulting in force field dependent preferred stacking modes; for example, in the cases of pyrene and tetracene. Our results provide a useful background study for using topology builders to model systems which rely on stacking of aromatic moieties, and are relevant in areas ranging from drug design to supramolecular assembly. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations: Advances and Applications)

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16 pages, 3490 KiB

Open AccessArticle

The Structural and Dynamical Properties of the Hydration of SNase Based on a Molecular Dynamics Simulation

by Hangxin Liu, Shuqing Xiang, Haomiao Zhu and Li Li

Molecules 2021, 26(17), 5403; https://doi.org/10.3390/molecules26175403 - 5 Sep 2021

Cited by 6 | Viewed by 3528

Abstract

The dynamics of protein–water fluctuations are of biological significance. Molecular dynamics simulations were performed in order to explore the hydration dynamics of staphylococcal nuclease (SNase) at different temperatures and mutation levels. A dynamical transition in hydration water (at ~210 K) can trigger larger-amplitude [...] Read more.

The dynamics of protein–water fluctuations are of biological significance. Molecular dynamics simulations were performed in order to explore the hydration dynamics of staphylococcal nuclease (SNase) at different temperatures and mutation levels. A dynamical transition in hydration water (at ~210 K) can trigger larger-amplitude fluctuations of protein. The protein–water hydrogen bonds lost about 40% in the total change from 150 K to 210 K, while the Mean Square Displacement increased by little. The protein was activated when the hydration water in local had a comparable trend in making hydrogen bonds with protein– and other waters. The mutations changed the local chemical properties and the hydration exhibited a biphasic distribution, with two time scales. Hydrogen bonding relaxation governed the local protein fluctuations on the picosecond time scale, with the fastest time (24.9 ps) at the hydrophobic site and slowest time (40.4 ps) in the charged environment. The protein dynamic was related to the water’s translational diffusion via the relaxation of the protein–water’s H-bonding. The structural and dynamical properties of protein–water at the molecular level are fundamental to the physiological and functional mechanisms of SNase. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations: Advances and Applications)

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17 pages, 6704 KiB

Open AccessArticle

Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study

by Mohammad G. Al-Thiabat, Amirah Mohd Gazzali, Noratiqah Mohtar, Vikneswaran Murugaiyah, Ezatul Ezleen Kamarulzaman, Beow Keat Yap, Noorsaadah Abd Rahman, Rozana Othman and Habibah A. Wahab

Molecules 2021, 26(17), 5304; https://doi.org/10.3390/molecules26175304 - 31 Aug 2021

Cited by 17 | Viewed by 3901

Abstract

Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. [...] Read more.

Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. In this study, FA was conjugated to beta-cyclodextrin (βCD) and subjected to in silico analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability for the conjugated system compared to unconjugated and apo systems (ligand free). Docking studies revealed that the conjugated FA bound into the active site of FRα with a docking score (free binding energy < −15 kcal/mol), with a similar binding pose to that of unconjugated FA. Subsequent analyses from molecular dynamics (MD) simulations, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) demonstrated that FA and FA–βCDs created more dynamically stable systems with FRα than the apo-FRα system. All systems reached equilibrium with stable RMSD values ranging from 1.9–2.4 Å and the average residual fluctuation values of the FRα backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 Å with a consistent Rg value of around 16.8 Å throughout the MD simulation time (0–100 ns). The conjugation with βCD improved the stability and decreased the mobility of all the residues (except residues 149–151) compared to FA–FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA), and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations: Advances and Applications)

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19 pages, 5502 KiB

Open AccessArticle

Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors

by Beatriz Hernández-Ochoa, Gabriel Navarrete-Vázquez, Rodrigo Aguayo-Ortiz, Paulina Ortiz-Ramírez, Laura Morales-Luna, Víctor Martínez-Rosas, Abigail González-Valdez, Fernando Gómez-Chávez, Sergio Enríquez-Flores, Carlos Wong-Baeza, Isabel Baeza-Ramírez, Verónica Pérez de la Cruz and Saúl Gómez-Manzo

Molecules 2021, 26(16), 4955; https://doi.org/10.3390/molecules26164955 - 16 Aug 2021

Cited by 7 | Viewed by 3357

Abstract

Helicobacter pylori (H. pylori) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies [...] Read more.

Helicobacter pylori (H. pylori) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies have several problems including antibiotics resistance. Therefore, new practical options to eliminate this bacterium, and its induced affections, are required to avoid morbidity and mortality worldwide. One strategy in the search for new drugs is to detect compounds that inhibit a limiting step in a central metabolic pathway of the pathogen of interest. In this work, we tested 55 compounds to gain insights into their possible use as new inhibitory drugs of H. pylori glucose-6-phosphate dehydrogenase (HpG6PD) activity. The compounds YGC-1; MGD-1, MGD-2; TDA-1; and JMM-3 with their respective scaffold 1,3-thiazolidine-2,4-dione; 1H-benzimidazole; 1,3-benzoxazole, morpholine, and biphenylcarbonitrile showed the best inhibitory activity (IC₅₀ = 310, 465, 340, 204 and 304 μM, respectively). We then modeled the HpG6PD protein by homology modeling to conduct an in silico study of the chemical compounds and discovers its possible interactions with the HpG6PD enzyme. We found that compounds can be internalized at the NADP⁺ catalytic binding site. Hence, they probably exert a competitive inhibitory effect with NADP⁺ and a non-competitive or uncompetitive effect with G6P, that of the compounds binding far from the enzyme’s active site. Based on these findings, the tested compounds inhibiting HpG6PD represent promising novel drug candidates against H. pylori. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations: Advances and Applications)

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15 pages, 14772 KiB

Open AccessArticle

Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach

by Richelly Cardoso, Renan Valente, Clauber Henrique Souza da Costa, João Lidio da S. Gonçalves Vianez, Jr., Kauê Santana da Costa, Fábio Alberto de Molfetta and Cláudio Nahum Alves

Molecules 2021, 26(10), 2875; https://doi.org/10.3390/molecules26102875 - 12 May 2021

Cited by 17 | Viewed by 5082

Abstract

Tyrosinases belong to the functional copper-containing proteins family, and their structure contains two copper atoms, in the active site, which are coordinated by three histidine residues. The biosynthesis of melanin in melanocytes has two stages depending on the actions of the natural substrates [...] Read more.

Tyrosinases belong to the functional copper-containing proteins family, and their structure contains two copper atoms, in the active site, which are coordinated by three histidine residues. The biosynthesis of melanin in melanocytes has two stages depending on the actions of the natural substrates L-DOPA and L-tyrosine. The dysregulation of tyrosinase is involved in skin cancer initiation. In the present study, using molecular modeling tools, we analyzed the inhibition activity of tyrosinase activity using kojic acid (KA) derivatives designed from aromatic aldehydes and malononitrile. All derivatives showed conformational affinity to the enzyme active site, and a favorable distance to chelate the copper ion, which is essential for enzyme function. Molecular dynamics simulations revealed that the derivatives formed promising complexes, presenting stable conformations with deviations between 0.2 and 0.35 Å. In addition, the investigated KA derivatives showed favorable binding free energies. The most stable KA derivatives showed the following binding free energies: −17.65 kcal mol⁻¹ (D6), −18.07 kcal mol⁻¹ (D2), −18.13 (D5) kcal mol⁻¹, and −10.31 kcal mol⁻¹ (D4). Our results suggest that these derivatives could be potent competitive inhibitors of the natural substrates of L-DOPA (−12.84 kcal mol⁻¹) and L-tyrosine (−9.04 kcal mol⁻¹) in melanogenesis. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations: Advances and Applications)

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