scholarly journals Electrostatic Interactions with Choline and Phosphate Groups Regulate Cisplatin Permeation through a Dioleoylphosphocholine Bilayer

2020 ◽  
Author(s):  
Lorena Ruano ◽  
Gustavo Cárdenas ◽  
Juan Jose Nogueira
Keyword(s):  
Free Energy ◽  
Lipid Bilayers ◽  
Long Range ◽  
Electrostatic Interactions ◽  
Umbrella Sampling ◽  
Energy Minimum ◽  
Free Energy Minimum ◽  
Dynamics Simulations ◽  
First Moment ◽  
Phosphate Groups

The investigation of the intermolecular interactions between platinum-based anticancer drugs and lipid bilayers is of special relevance to unveil the mechanisms involved in different steps of the mode of action of these drugs. We have simulated the permeation of cisplatin through a model membrane composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids by means of umbrella sampling classical molecular dynamics simulations. The initial physisorption of cisplatin in the polar region of the membrane is controlled, in a first moment, by long-range electrostatic interactions with the choline groups, which trap the drug in a shallow free-energy minimum. Then, cisplatin is driven to a deeper free-energy minimum by long-range electrostatic interactions with the phosphate groups. From this minimum to the middle of the bilayer the electrostatic repulsion between cisplatin and the choline groups partially cancels out the electrostatic attraction between cisplatin and the phosphate groups, inducing a general drop of the total interaction with the polar heads. In addition, the attractive interactions with the non-polar tails, which are dominated by van der Waals contributions, gain significance. The large energy barrier found when going from the global minimum to the middle of the membrane indicates that the non-electrostatic interactions between the drug and the non-polar tails are badly reproduced by the fixed point-charge force field used here, and that the introduction of polarization effects are likely necessary.

scholarly journals Electrostatic Interactions with Choline and Phosphate Groups Regulate Cisplatin Permeation through a Dioleoylphosphocholine Bilayer

2020 ◽  
Author(s):  
Lorena Ruano ◽  
Gustavo Cárdenas ◽  
Juan Jose Nogueira
Keyword(s):  
Free Energy ◽  
Lipid Bilayers ◽  
Long Range ◽  
Electrostatic Interactions ◽  
Umbrella Sampling ◽  
Energy Minimum ◽  
Free Energy Minimum ◽  
Dynamics Simulations ◽  
First Moment ◽  
Phosphate Groups

The investigation of the intermolecular interactions between platinum-based anticancer drugs and lipid bilayers is of special relevance to unveil the mechanisms involved in different steps of the mode of action of these drugs. We have simulated the permeation of cisplatin through a model membrane composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids by means of umbrella sampling classical molecular dynamics simulations. The initial physisorption of cisplatin in the polar region of the membrane is controlled, in a first moment, by long-range electrostatic interactions with the choline groups, which trap the drug in a shallow free-energy minimum. Then, cisplatin is driven to a deeper free-energy minimum by long-range electrostatic interactions with the phosphate groups. From this minimum to the middle of the bilayer the electrostatic repulsion between cisplatin and the choline groups partially cancels out the electrostatic attraction between cisplatin and the phosphate groups, inducing a general drop of the total interaction with the polar heads. In addition, the attractive interactions with the non-polar tails, which are dominated by van der Waals contributions, gain significance. The large energy barrier found when going from the global minimum to the middle of the membrane indicates that the non-electrostatic interactions between the drug and the non-polar tails are badly reproduced by the fixed point-charge force field used here, and that the introduction of polarization effects are likely necessary.

scholarly journals The Permeation Mechanism of Cisplatin through a Dioleoylphosphocholine Bilayer

2021 ◽  
Author(s):  
Lorena Ruano ◽  
Gustavo Cárdenas ◽  
Juan Jose Nogueira
Keyword(s):  
Lipid Bilayers ◽  
Long Range ◽  
Electrostatic Interactions ◽  
Lipid Membrane ◽  
Umbrella Sampling ◽  
Hydrogen Bond Interactions ◽  
Dynamics Simulations ◽  
First Moment ◽  
Special Relevance ◽  
Phosphate Groups

The investigation of the intermolecular interactions between platinum-based anticancer drugs and lipid bilayers is of special relevance to unveil the mechanisms involved in different steps of the anticancer mode of action of these drugs. We have simulated the permeation of cisplatin through a model membrane composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids by means of umbrella sampling classical molecular dynamics simulations. The initial physisorption of cisplatin into the polar region of the lipid membrane is controlled, in a first moment, by long-range electrostatic interactions with the choline groups and, in a second step, by long-range electrostatic and hydrogen bond interactions with the phosphate groups. The second half of the permeation pathway, in which cisplatin diffuses through the nonpolar region of the bilayer, is characterized by the drop of the interactions with the polar heads and the rise of attractive interactions with the non-polar tails, which are dominated by van der Waals contributions.

scholarly journals Molecular dynamics simulations of charged and neutral lipid bilayers: treatment of electrostatic interactions.

2003 ◽  
Vol 50 (3) ◽  
pp. 789-798 ◽  
Author(s):  
Tomasz Róg ◽  
Krzysztof Murzyn ◽  
Marta Pasenkiewicz-Gierula
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Lipid Bilayers ◽  
Long Range ◽  
Electrostatic Interactions ◽  
Md Simulations ◽  
Computational Method ◽  
Simulation Protocol ◽  
Speed Up ◽  
Dynamics Simulations

Molecular dynamics (MD) simulations complement experimental methods in studies of the structure and dynamics of lipid bilayers. The choice of algorithms employed in this computational method represents a trade-off between the accuracy and real calculation time. The largest portion of the simulation time is devoted to calculation of long-range electrostatic interactions. To speed-up evaluation of these interactions, various approximations have been used. The most common ones are the truncation of long-range interactions with the use of cut-offs, and the particle-mesh Ewald (PME) method. In this study, several multi-nanosecond cut-off and PME simulations were performed to establish the influence of the simulation protocol on the bilayer properties. Two bilayers were used. One consisted of neutral phosphatidylcholine molecules. The other was a mixed lipid bilayer consisting of neutral phosphatidylethanolamine and negatively charged phosphatidylglycerol molecules. The study shows that the cut-off simulation of a bilayer containing charge molecules generates artefacts; in particular the mobility and order of the charged molecules are vastly different from those determined experimentally. In the PME simulation, the bilayer properties are in general agreement with experimental data. The cut-off simulation of bilayers containing only uncharged molecules does not generate artefacts, nevertheless, the PME simulation gives generally better agreement with experimental data.

Displacement of carbonates in Ca2UO2(CO3)3 by amidoxime-based ligands from free-energy simulations

2018 ◽  
Vol 47 (5) ◽  
pp. 1604-1613 ◽  
Author(s):  
Bo Li ◽  
Chad Priest ◽  
De-en Jiang
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Umbrella Sampling ◽  
Nacl Solution ◽  
Classical Molecular Dynamics ◽  
Energy Profiles ◽  
Energy Simulations ◽  
Dynamics Simulations ◽  
Free Energy Profiles

Classical molecular dynamics simulations coupled with umbrella sampling reveal the atomistic processes and free-energy profiles of the displacement of carbonate groups in the Ca2UO2(CO3)3 complex by amidoxime-based ligands in a 0.5 M NaCl solution.

scholarly journals Molecular dynamics simulations and free energy profile of Paracetamol in DPPC and DMPC lipid bilayers

2014 ◽  
Vol 126 (3) ◽  
pp. 637-647 ◽  
Author(s):  
YOUSEF NADEMI ◽  
SEPIDEH AMJAD IRANAGH ◽  
ABBAS YOUSEFPOUR ◽  
SEYEDEH ZAHRA MOUSAVI ◽  
HAMID MODARRESS
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Lipid Bilayers ◽  
Energy Profile ◽  
Free Energy Profile ◽  
Dynamics Simulations

scholarly journals Entropic Path Sampling: Computational Protocol to Evaluate Entropic Profile along a Reaction Path

2021 ◽  
Author(s):  
Zhi-Xin Qin ◽  
Matthew Tremblay ◽  
Xin Hong ◽  
Zhongyue Yang
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Reaction Path ◽  
Product Formation ◽  
Conformational Flexibility ◽  
Model Reaction ◽  
Energy Minimum ◽  
Path Sampling ◽  
Free Energy Minimum ◽  
Computational Protocol

Fleeting intermediates constitute dynamically-stepwise mechanisms. They have been characterized in molecular dynamics trajectories, but whether these intermediates form a free energy minimum to become entropic intermediate remains elusively defined. We developed a computational protocol known as entropic path sampling to evaluate the entropic variation of reacting species along a reaction path based on an ensemble of trajectories. Using cyclopentadiene dimerization as a model reaction, we observed a shallow entropic trap (–T∆S = –0.8 kcal/mol) along the reaction path which originates from an enhanced conformational flexibility as the reacting species enter into a flat energy region. As the reacting species further approach product formation, unfavorable entropic restriction fails to offset the potential energy drop, resulting in no free energy minimum along the post-TS pathway. Our results show that cyclopentadiene dimerization involves an entropic trap that leads to dynamic intermediates with elongated lifetime, but the reaction does not involve entropic intermediates.

scholarly journals Structural and energetic analysis of metastable intermediate states in the E1P–E2P transition of Ca2+-ATPase

2021 ◽  
Vol 118 (40) ◽  
pp. e2105507118
Author(s):  
Chigusa Kobayashi ◽  
Yasuhiro Matsunaga ◽  
Jaewoon Jung ◽  
Yuji Sugita
Keyword(s):  
Free Energy ◽  
Structural Changes ◽  
Umbrella Sampling ◽  
X Ray Crystallography ◽  
Atomic Structures ◽  
Energy Profiles ◽  
Intermediate States ◽  
Before And After ◽  
Energetic Analysis ◽  
Dynamics Simulations

Sarcoplasmic reticulum (SR) Ca2+-ATPase transports two Ca2+ ions from the cytoplasm to the SR lumen against a large concentration gradient. X-ray crystallography has revealed the atomic structures of the protein before and after the dissociation of Ca2+, while biochemical studies have suggested the existence of intermediate states in the transition between E1P⋅ADP⋅2Ca2+ and E2P. Here, we explore the pathway and free energy profile of the transition using atomistic molecular dynamics simulations with the mean-force string method and umbrella sampling. The simulations suggest that a series of structural changes accompany the ordered dissociation of ADP, the A-domain rotation, and the rearrangement of the transmembrane (TM) helices. The luminal gate then opens to release Ca2+ ions toward the SR lumen. Intermediate structures on the pathway are stabilized by transient sidechain interactions between the A- and P-domains. Lipid molecules between TM helices play a key role in the stabilization. Free energy profiles of the transition assuming different protonation states suggest rapid exchanges between Ca2+ ions and protons when the Ca2+ ions are released toward the SR lumen.

MOLECULAR DYNAMICS SIMULATIONS OF DNA DIMERS BASED ON REPLICA-EXCHANGE UMBRELLA SAMPLING II: FREE ENERGY ANALYSIS

2005 ◽  
Vol 04 (02) ◽  
pp. 433-448 ◽  
Author(s):  
KATSUMI MURATA ◽  
YUJI SUGITA ◽  
YUKO OKAMOTO
Keyword(s):  
Free Energy ◽  
Energy Analysis ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Sequence Dependence ◽  
Reaction Coordinates ◽  
Energy Profiles ◽  
Dynamics Simulations ◽  
Free Energy Analysis ◽  
Good Agreement

The free energy change of the stacking process of DNA dimers has been investigated by potential of mean force (PMF) calculations. Two reaction coordinates were considered. One is the distance R between the glycosidic nitrogen atoms of the bases. The other is the pseudo dihedral angle X (N–Cl′–Cl′–N) . All 16 possible DNA dimers composed of the adenine, cytosine, guanine, or thymine bases in 5′ and 3′ positions were considered. From the free energy profiles, we observed good stacking for all DNA dimers and sequence-dependent stacking stability. This sequence dependence of the stacking free energy is in good agreement with the experimental results. We also observed that the PMF is the lowest at R = 4.0~4.4 Å and X = 20~40° for all the DNA dimers except for the dGpdA dimer. These values are close to those of the canonical B-DNA (4.4 Å and 29°).

scholarly journals The 2-D Cluster Variation Method: Topography Illustrations and Their Enthalpy Parameter Correlations

Entropy ◽  
2021 ◽  
Vol 23 (3) ◽  
pp. 319
Author(s):  
Alianna J. Maren
Keyword(s):  
Free Energy ◽  
Nearest Neighbor ◽  
Activation Enthalpy ◽  
Cluster Variation Method ◽  
Variation Method ◽  
Energy Minimum ◽  
Dimensional Parameter ◽  
Free Energy Minimum ◽  
Interaction Enthalpy ◽  
Cluster Variation

One of the biggest challenges in characterizing 2-D image topographies is finding a low-dimensional parameter set that can succinctly describe, not so much image patterns themselves, but the nature of these patterns. The 2-D cluster variation method (CVM), introduced by Kikuchi in 1951, can characterize very local image pattern distributions using configuration variables, identifying nearest-neighbor, next-nearest-neighbor, and triplet configurations. Using the 2-D CVM, we can characterize 2-D topographies using just two parameters; the activation enthalpy (ε0) and the interaction enthalpy (ε1). Two different initial topographies (“scale-free-like” and “extreme rich club-like”) were each computationally brought to a CVM free energy minimum, for the case where the activation enthalpy was zero and different values were used for the interaction enthalpy. The results are: (1) the computational configuration variable results differ significantly from the analytically-predicted values well before ε1 approaches the known divergence as ε1→0.881, (2) the range of potentially useful parameter values, favoring clustering of like-with-like units, is limited to the region where ε0<3 and ε1<0.25, and (3) the topographies in the systems that are brought to a free energy minimum show interesting visual features, such as extended “spider legs” connecting previously unconnected “islands,” and as well as evolution of “peninsulas” in what were previously solid masses.

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