scholarly journals Combining free energy simulations and NMR chemical-shift perturbation to identify transient cation-π contacts in proteins

2019 ◽  
Author(s):  
André A. O. Reis ◽  
Raphael S. R. Sayegh ◽  
Sandro R. Marana ◽  
Guilherme M. Arantes
Keyword(s):  
Free Energy ◽  
Chemical Shift ◽  
Catalytic Domain ◽  
Chemical Shifts ◽  
Umbrella Sampling ◽  
Terminal Segment ◽  
Functional Roles ◽  
Energy Profiles ◽  
Energy Simulations ◽  
Dynamics Simulations

AbstractFlexible protein regions containing cationic and aromatic side-chains exposed to solvent may form transient cation-π interactions with structural and functional roles. To evaluate their stability and identify important intramolecular cation-π contacts, a combination of free energy profiles estimated from umbrella sampling with molecular dynamics simulations and chemical shift perturbations (CSP) obtained from NMR experiments is applied here to the complete catalytic domain of human phosphatase Cdc25B. This protein is a good model system for transient cation-π interactions as it contains only one Trp residue (W550) in the disordered C-terminal segment and a total of 17 Arg residues, many exposed to solvent. Eight putative Arg-Trp pairs were simulated here. Only R482 and R544 show bound profiles corresponding to important transient cation-π interactions, while the others have dissociative or almost flat profiles. These results are corroborated by CSP analysis of three Cdc25B point mutants (W550A, R482A and R544A) disrupting cation-π contacts. The proposed validation of statistically representative molecular simulations by NMR spectroscopy could be applied to identify transient contacts of proteins in general but carefully, as NMR chemical shifts are sensitive to changes in both molecular contacts and conformational distributions.

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 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 Reconstructing the Free Energy Profiles Describing the Switching Mechanism of a pH-Dependent DNA Nanodevice from ABMD Simulations

2021 ◽  
Vol 11 (9) ◽  
pp. 4052
Author(s):  
Alice Romeo ◽  
Mattia Falconi ◽  
Alessandro Desideri ◽  
Federico Iacovelli
Keyword(s):  
Free Energy ◽  
Double Helix ◽  
Minimum Energy ◽  
Switching Mechanism ◽  
Linker Length ◽  
Energy Profiles ◽  
Functional Dna ◽  
Triplex Forming Oligonucleotide ◽  
Dynamics Simulations ◽  
Free Energy Profiles

The pH-responsive behavior of six triple-helix DNA nanoswitches, differing in the number of protonation centers (two or four) and in the length of the linker (5, 15 or 25 bases), connecting the double-helical region to the single-strand triplex-forming region, was characterized at the atomistic level through Adaptively Biased Molecular Dynamics simulations. The reconstruction of the free energy profiles of triplex-forming oligonucleotide unbinding from the double helix identified a different minimum energy path for the three diprotic nanoswitches, depending on the length of the connecting linker and leading to a different per-base unbinding profile. The same analyses carried out on the tetraprotic switches indicated that, in the presence of four protonation centers, the unbinding process occurs independently of the linker length. The simulation data provide an atomistic explanation for previously published experimental results showing, only in the diprotic switch, a two unit increase in the pKa switching mechanism decreasing the linker length from 25 to 5 bases, endorsing the validity of computational methods for the design and refinement of functional DNA nanodevices.

Relation between the NMR data and the pseudorotational free-energy profile for oxolane

2019 ◽  
Vol 18 (02) ◽  
pp. 1950012 ◽  
Author(s):  
Wojciech Plazinski ◽  
Karolina Gaweda ◽  
Anita Plazinska
Keyword(s):  
Free Energy ◽  
Quantitative Description ◽  
Coupling Constants ◽  
Biologically Relevant ◽  
Dna And Rna ◽  
Energy Profiles ◽  
Nmr Data ◽  
Biologically Relevant Molecules ◽  
Dynamics Simulations ◽  
Two State Model

The conformation of five-membered furanose rings is a crucial issue for the structural analysis of many biologically-relevant molecules, including DNA and RNA. Oxolane can be treated as a prototypical furanose, composed only of saturated unsubstituted ring. In spite of its structural simplicity, providing the accurate quantitative description of the oxolane conformational features remains a great challenge for both the experimental and theoretical techniques. Here we show the method of recovering the free-energy profiles describing the conformational equilibrium in the oxolane ring (i.e. pseudorotation) based on the experimentally-inferred NMR data ([Formula: see text] coupling constants). The results remain in agreement with the quantum-mechanical-based molecular dynamics simulations and emphasize the large contributions of all ring conformers, even those located at the free-energy barriers. This includes the significant populations of limiting 3T2/2T3 and OE/EO shapes. Our findings provide another example of a poor applicability of the two-state model, which is routinely applied to analyze the NMR data in terms of population of different ring conformers.

Finite-temperature effects in enzymatic reactions — Insights from QM/MM free-energy simulations

2009 ◽  
Vol 87 (10) ◽  
pp. 1322-1337 ◽  
Author(s):  
Hans Martin Senn ◽  
Johannes Kästner ◽  
Jürgen Breidung ◽  
Walter Thiel
Keyword(s):  
Free Energy ◽  
Finite Temperature ◽  
Temperature Effects ◽  
Density Functional ◽  
Umbrella Sampling ◽  
Chorismate Mutase ◽  
Enzymatic Reactions ◽  
Energy Data ◽  
Energy Simulations ◽  
Entropic Contribution

We report potential-energy and free-energy data for three enzymatic reactions: carbon–halogen bond formation in fluorinase, hydrogen abstraction from camphor in cytochrome P450cam, and chorismate-to-prephenate Claisen rearrangement in chorismate mutase. The results were obtained by combined quantum mechanics/molecular mechanics (QM/MM) optimizations and two types of QM/MM free-energy simulations (free-energy perturbation and umbrella sampling) using semi-empirical or density-functional QM methods. Based on these results and our previously published free-energy data on electrophilic substitution in para-hydroxybenzoate hydroxylase, we discuss the importance of finite-temperature effects in the chemical step of enzyme reactions. We find that the entropic contribution to the activation barrier is generally rather small, usually of the order of 5 kJ mol–1 or less, consistent with the notion that enzymes bind and pre-organize the reactants in the active site. A somewhat larger entropic contribution is encountered in the case of chorismate mutase where the pericyclic transition state is intrinsically more rigid than the chorismate reactant (also in the enzyme). The present results suggest that barriers from QM/MM geometry optimization may often be close to free-energy barriers for the chemical step in enzymatic reactions.

The molecular mechanism of ligand unbinding from the human telomeric G-quadruplex by steered molecular dynamics and umbrella sampling simulations

2015 ◽  
Vol 17 (19) ◽  
pp. 12857-12869 ◽  
Author(s):  
Jia-Kai Zhou ◽  
Dah-Yen Yang ◽  
Sheh-Yi Sheu
Keyword(s):  
Mechanical Properties ◽  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Mechanism ◽  
Steered Molecular Dynamics ◽  
Umbrella Sampling ◽  
Energy Profiles ◽  
G Quadruplex ◽  
Free Energy Profiles

The mechanical properties and kinetic pathways of the ligand BMVC unbinding from the G-quadruplex were investigated via the computation of free energy profiles.

scholarly journals Understanding the essential proton-pumping kinetic gates and decoupling mutations in cytochrome c oxidase

2017 ◽  
Vol 114 (23) ◽  
pp. 5924-5929 ◽  
Author(s):  
Ruibin Liang ◽  
Jessica M. J. Swanson ◽  
Mårten Wikström ◽  
Gregory A. Voth
Keyword(s):  
Free Energy ◽  
Molecular Mechanisms ◽  
Proton Pumping ◽  
Amino Acid Residues ◽  
Reactive Molecular Dynamics ◽  
Chemical Catalysis ◽  
Energy Profiles ◽  
High Proton ◽  
Pumping Efficiency ◽  
Dynamics Simulations

Cytochrome c oxidase (CcO) catalyzes the reduction of oxygen to water and uses the released free energy to pump protons against the transmembrane proton gradient. To better understand the proton-pumping mechanism of the wild-type (WT) CcO, much attention has been given to the mutation of amino acid residues along the proton translocating D-channel that impair, and sometimes decouple, proton pumping from the chemical catalysis. Although their influence has been clearly demonstrated experimentally, the underlying molecular mechanisms of these mutants remain unknown. In this work, we report multiscale reactive molecular dynamics simulations that characterize the free-energy profiles of explicit proton transport through several important D-channel mutants. Our results elucidate the mechanisms by which proton pumping is impaired, thus revealing key kinetic gating features in CcO. In the N139T and N139C mutants, proton back leakage through the D-channel is kinetically favored over proton pumping due to the loss of a kinetic gate in the N139 region. In the N139L mutant, the bulky L139 side chain inhibits timely reprotonation of E286 through the D-channel, which impairs both proton pumping and the chemical reaction. In the S200V/S201V double mutant, the proton affinity of E286 is increased, which slows down both proton pumping and the chemical catalysis. This work thus not only provides insight into the decoupling mechanisms of CcO mutants, but also explains how kinetic gating in the D-channel is imperative to achieving high proton-pumping efficiency in the WT CcO.

scholarly journals Ring Puckering Landscapes of Glycosaminoglycan-Related Monosaccharides from Molecular Dynamics Simulations

2019 ◽  
Author(s):  
Irfan Alibay ◽  
Richard Bryce
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Biological Function ◽  
Enhanced Sampling ◽  
Energy Profiles ◽  
Ring Puckering ◽  
Dynamics Simulations ◽  
Ring Pucker ◽  
Free Energy Profiles

<p>The conformational flexibility of the glycosaminoglycans (GAGs) are known to be key in their binding and biological function, for example in regulating coagulation and cell growth. In this work, we employ enhanced sampling molecular dynamics simulations to probe the ring conformations of GAG-related monosaccharides, including a range of acetylated and sulfated GAG residues. We first perform unbiased MD simulations of glucose anomers and the epimers glucoronate and iduronate. These calculations indicate that in some cases, an excess of 15 microseconds are required for adequate sampling of ring pucker due to the high energy barriers between states. However, by applying our recently developed msesMD simulation method (multidimensional swarm enhanced sampling molecular dynamics), we were able to quantitatively and rapidly reproduce these ring pucker landscapes. From msesMD simulations, the puckering free energy profiles were then compared for eleven monosaccharides found in GAGs; this includes to our knowledge the first simulation study of sulfation effects on GalNAc ring puckering. For the force field employed, we find that in general the calculated pucker free energy profiles for sulfated sugars were similar to the corresponding unsulfated profiles. This accords with recent experimental studies suggesting that variation in ring pucker of sulfated GAG residues is primarily dictated by interactions with surrounding residues rather than by intrinsic conformational preference. As an exception to this, however, we predict that 4-O-sulfation of GalNAc leads to reduced ring rigidity, with a significant lowering in energy of the <sup>1</sup>C<sub>4</sub> ring conformation; this observation may have implications for understanding the structural basis of the biological function of GalNAc-containing glycosaminoglycans such as dermatan sulfate.</p>

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