The intercalation of imidazoacridinones into DNA induces conformational changes in their side chain.

Imidazoacridinones (IAs) are a new group of highly active antitumor compounds. The intercalation of the IA molecule into DNA is the preliminary step in the mode of action of these compounds. There are no experimental data about the structure of an intercalation complex formed by imidazoacridinones. Therefore the design of new potentially better compounds of this group should employ the molecular modelling techniques. The results of molecular dynamics simulations performed for four IA analogues are presented. Each of the compounds was studied in two systems: i) in water, and ii) in the intercalation complex with dodecamer duplex d(GCGCGCGCGCGC)2. Significant differences in the conformation of the side chain in the two environments were observed for all studied IAs. These changes were induced by electrostatic as well as van der Waals interactions between the intercalator and DNA. Moreover, the results showed that the geometry of the intercalation complex depends on: i) the chemical constitution of the side chain, and ii) the substituent in position 8 of the ring system.

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The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations.

Acta Biochimica Polonica ◽

10.18388/abp.2000_4061 ◽

2000 ◽

Vol 47 (1) ◽

pp. 47-57 ◽

Cited By ~ 3

Author(s):

J Mazerski ◽

I Antonini ◽

S Martelli

Keyword(s):

Molecular Dynamics ◽

Rational Design ◽

Md Simulations ◽

Ring System ◽

Side Chain ◽

Side Chains ◽

Intercalation Complex ◽

Highly Active ◽

Simulation Techniques ◽

Dynamics Simulations

Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor compounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficient condition for antitumor activity of these compounds. Rational design of new compounds of this chemotype requires knowledge about the structure of the intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) may provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and position of side chains. Each of the compounds was simulated in two systems: i) in water, and ii) in the intercalation complex with the dodecamer duplex d(GCGCGCGCGCGC)2. The orientation of the side chain in relation to the ring system is determined by the position of its attachment. Orientation of the ring system inside the intercalation cavity depends on the number and position of side chain(s). The conformations of the side chain(s) of all PATs studied in the intercalation complex were found to be very similar to those observed in water.

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Molecular dynamics simulations reveal the selectivity mechanism of structurally similar agonists to TLR7 and TLR8

10.1101/2021.11.15.468604 ◽

2021 ◽

Author(s):

Xiaoyu Wang ◽

Yu Chen ◽

Steven Zhang ◽

Jinxia Nancy Deng

Keyword(s):

Small Molecule ◽

Van Der Waals ◽

Biological Response ◽

Binding Pocket ◽

Van Der Waals Interactions ◽

Side Chain ◽

Dynamic Simulations ◽

Hydrophobic Nature ◽

Dynamics Simulations ◽

Small Molecule Modulators

TLR7 and TLR8 are key members of the Toll-like receptor family, playing crucial roles in the signaling pathways of innate immunity, and thus become attractive therapeutic targets of many diseases including infections and cancer. Although TLR7 and TLR8 show a highly degree of sequence homology, their biological response to small molecule binding is very different. Aiming to understand the mechanism of selective profiles of small molecule modulators against TLR7 and TLR8, we carried out molecular dynamic simulations on three imidazoquinoline derivatives bound to the receptors separately. They are Resiquimod (R), Hybrid-2 (H), and Gardiquimod (G), selective agonists of TLR7 and TLR8. Our MD trajectories indicated that in the complex of TLR7-R and TLR7-G, the two chains forming the TLR7 dimer tended to remain “open” conformation, while the rest systems maintained in the closed format. The agonists R, H, and G developed conformational deviation mainly on the aliphatic tail. Furthermore, we attempted to quantify the selectivity between TLR7 and TLR8 by binding free energies via MM-GBSA method. It showed that the three selected modulators were more favorable for TLR7 than TLR8, and the ranking from the strongest to the weakest was H, R and G, aligning well with experiment data. In the TLR7, the flexible and hydrophobic aliphatic side chain of H has stronger van der Waals interactions with Val381 and Phe351 but only pick up interaction with one amino acid residue i.e. Tyr353 of TLR8. Unsurprisingly, the positively charged side chain of G has less favor interaction with Ile585 of TLR7 and Val573 of TLR8 explaining G is weak agonist in both TLR7 and TLR8. All three imidazoquinolines can form stable hydrogen bonds with Asp555 of TLR7 and the corresponding Asp543 of TLR8. In brief, the set of total 400ns MD studies sheds light on the potential selective mechanisms of agonists towards TLR7 and TLR8, indicating the van der Waals interaction as the driving force for the agonists binding, thus provides us insights for more potent and selective modulators to cooperate with the hydrophobic nature of the binding pocket.

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Hidden electrostatic basis of dynamic allostery in a PDZ domain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1705311114 ◽

2017 ◽

Vol 114 (29) ◽

pp. E5825-E5834 ◽

Cited By ~ 44

Author(s):

Amit Kumawat ◽

Suman Chakrabarty

Keyword(s):

Ligand Binding ◽

Conformational Changes ◽

Electrostatic Interactions ◽

Pdz Domain ◽

Allosteric Modulation ◽

Side Chain ◽

Salt Bridges ◽

Population Shift ◽

Domain Protein ◽

Dynamics Simulations

Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to the traditionally used structure-based parameters. There is a significant population shift in the hydrogen-bonded network and salt bridges involving side chains on ligand binding. The ligand creates a local energetic perturbation that propagates in the form of dominolike changes in interresidue interaction pattern. There are significant changes in the nature of specific interactions (nonpolar/polar) between interresidue contacts and accompanied side-chain reorientations that drive the major redistribution of energy. Interestingly, this internal redistribution and rewiring of side-chain interactions led to large cancellations resulting in small change in the overall enthalpy of the protein, thus making it difficult to detect experimentally. In contrast to the prevailing focus on the entropic or dynamic effects, we show that the internal redistribution and population shift in specific electrostatic interactions drive the allosteric modulation in the PDZ3 domain protein.

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Unraveling the Mechanism of a LOV Domain Optogenetic Sensor: A Glutamine Lever Induces Unfolding of the Jα Helix

10.1101/2020.01.29.925040 ◽

2020 ◽

Author(s):

James N. Iuliano ◽

Jinnette Tolentino Collado ◽

Agnieszka A. Gil ◽

Pavithran T. Ravindran ◽

Andras Lukacs ◽

...

Keyword(s):

Structural Dynamics ◽

Conformational Changes ◽

Interdisciplinary Approach ◽

Site Directed Mutagenesis ◽

Side Chain ◽

Lov Domain ◽

Time Resolved ◽

Protein Structural Dynamics ◽

Dynamics Simulations ◽

Time Resolved Infrared Spectroscopy

AbstractLight-activated protein domains provide a convenient, modular, and genetically encodable sensor for optogenetics and optobiology. Although these domains have now been deployed in numerous systems, the precise mechanism of photoactivation and the accompanying structural dynamics that modulate output domain activity remain to be fully elucidated. In the C-terminal light, oxygen, voltage (LOV) domain of plant phototropins (LOV2), blue light activation leads to formation of an adduct between a conserved Cys residue and the embedded FMN chromophore, rotation of a conserved Gln (Q513), and unfolding of a helix (Jα-helix) which is coupled to the output partner. In the present work, we focus on the allosteric pathways leading to Jα helix unfolding in Avena sativa LOV2 (AsLOV2) using an interdisciplinary approach involving molecular dynamics simulations extending to 7 μs, time-resolved infrared spectroscopy, solution NMR spectroscopy, and in-cell optogenetic experiments. In the dark state, the side chain of N414 is hydrogen bonded to the backbone N-H of Q513. The simulations predict a lever-like motion of Q513 after Cys adduct formation resulting in loss of the interaction between the side chain of N414 and the backbone C=O of Q513, and formation of a transient hydrogen bond between the Q513 and N414 side chains. The central role of N414 in signal transduction was evaluated by site-directed mutagenesis supporting a direct link between Jα helix unfolding dynamics and the cellular function of the Zdk2-AsLOV2 optogenetic construct. Through this multifaceted approach, we show that Q513 and N414 are critical mediators of protein structural dynamics, linking the ultrafast (sub-ps) excitation of the FMN chromophore to the microsecond conformational changes that result in photoreceptor activation and biological function.

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MOLECULAR SIMULATIONS OF NEOCARZINOSTATIN CHROMOPHORE RELEASE MECHANISM

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633612500927 ◽

2012 ◽

Vol 11 (06) ◽

pp. 1357-1368 ◽

Cited By ~ 4

Author(s):

HUI YU ◽

XI ZHAO ◽

XIAN-LI FENG ◽

XUECHENG CHEN ◽

EWA BOROWIAK-PALEN ◽

...

Keyword(s):

Drug Delivery ◽

Molecular Dynamics ◽

Conformational Changes ◽

Sampling Method ◽

Side Chain ◽

Release Mechanism ◽

Carrier Protein ◽

Clinical Use ◽

Essential Dynamics ◽

Dynamics Simulations

Neocarzinostatin (NCS) is an antitumor chromophore carrier protein with many applications in clinical use such as drug delivery system; however, so far its chromophore-releasing mechanism remains unclear. In this contribution the process and pathway of the chromophore releasing from holoprotein are revealed by conventional molecular dynamics simulations and essential dynamics (ED) sampling method. The results are consistent with the model for ligand release proposed in [D. H. Chin et al., J Biol Chem281:16025, 2006]. The further analysis suggests that the conformational changes of loop 99–104 and motions of side-chain of residue Phe78 are important factors for chromophore release; the opening state of loop 99–104 is a precondition for the release of ligand.

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Histidine protonation and the activation of viral fusion proteins

Biochemical Society Transactions ◽

10.1042/bst0360043 ◽

2008 ◽

Vol 36 (1) ◽

pp. 43-45 ◽

Cited By ~ 46

Author(s):

Daniela S. Mueller ◽

Thorsten Kampmann ◽

Ragothaman Yennamalli ◽

Paul R. Young ◽

Bostjan Kobe ◽

...

Keyword(s):

Conformational Changes ◽

Envelope Protein ◽

Fusion Proteins ◽

Side Chain ◽

Viral Fusion ◽

Histidine Residues ◽

Local Environments ◽

Viral Fusion Proteins ◽

Dynamics Simulations

Many viral fusion proteins only become activated under mildly acidic condition (pH 4.5–6.5) close to the pKa of histidine side-chain protonation. Analysis of the sequences and structures of influenza HA (haemagglutinin) and flaviviral envelope glycoproteins has led to the identification of a number of histidine residues that are not only fully conserved themselves but have local environments that are also highly conserved [Kampmann, Mueller, Mark, Young and Kobe (2006) Structure 14, 1481–1487]. Here, we summarize studies aimed at determining the role, if any, that protonation of these potential switch histidine residues plays in the low-pH-dependent conformational changes associated with fusion activation of a flaviviral envelope protein. Specifically, we report on MD (Molecular Dynamics) simulations of the DEN2 (dengue virus type 2) envelope protein ectodomain sE (soluble E) performed under varied pH conditions designed to test the histidine switch hypothesis of Kampmann et al. (2006).

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Unexpected Enzyme TEM-126: Role of Mutation Asp179Glu

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.10.4280-4287.2005 ◽

2005 ◽

Vol 49 (10) ◽

pp. 4280-4287 ◽

Cited By ~ 14

Author(s):

J. Delmas ◽

F. Robin ◽

F. Bittar ◽

C. Chanal ◽

R. Bonnet

Keyword(s):

Escherichia Coli ◽

Conformational Changes ◽

Hydrolytic Activity ◽

Side Chain ◽

Omega Loop ◽

Synergy Test ◽

Dynamics Simulations ◽

Apparent Susceptibility ◽

Level Resistance

ABSTRACT The clinical isolate Escherichia coli CF884 exhibited low-level resistance to ceftazidime (4 μg/ml) by a positive double-disk synergy test and apparent susceptibility to cefuroxime, cefotaxime, cefepime, cefpirome, and aztreonam. The enzyme implicated in this phenotype was a novel 180-kb plasmid-encoded TEM-type extended-spectrum β-lactamase designated TEM-126 which harbors the mutations Asp179Glu and Met182Thr. TEM-126 exhibited significant hydrolytic activity (k cat, 2 s−1) and a Km value of 82 μM against ceftazidime. Molecular dynamics simulations suggested that the substitution Asp179Glu induces subtle conformational changes to the omega loop which may favor the insertion of ceftazidime in the binding site and the correct positioning of the crucial residue Glu166. Overall, these results highlight the remarkable plasticity of TEM enzymes, which can expand their activity against ceftazidime by the addition of one carbon atom in the side chain of residue 179.

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Influence of Flexible Side-Chains on the Breathing Phase Transition of Pillared Layer MOFs: A Force Field Investigation

10.26434/chemrxiv.11720679.v1 ◽

2020 ◽

Author(s):

Julian Keupp ◽

Johannes P. Dürholt ◽

Rochus Schmid

Keyword(s):

First Principles ◽

Good Accuracy ◽

Field Investigation ◽

Square Lattice ◽

Side Chain ◽

Second Step ◽

Side Chains ◽

Dynamics Simulations ◽

Complex Phenomena ◽

Closed Pore

The prototypical pillared layer MOFs, formed by a square lattice of paddle- wheel units and connected by dinitrogen pillars, can undergo a breathing phase transition by a “wine-rack” type motion of the square lattice. We studied this not yet fully understood behavior using an accurate first principles parameterized force field (MOF-FF) for larger nanocrystallites on the example of Zn 2 (bdc) 2 (dabco) [bdc: benzenedicarboxylate, dabco: (1,4-diazabicyclo[2.2.2]octane)] and found clear indi- cations for an interface between a closed and an open pore phase traveling through the system during the phase transformation [Adv. Theory Simul. 2019, 2, 11]. In conventional simulations in small supercells this mechanism is prevented by periodic boundary conditions (PBC), enforcing a synchronous transformation of the entire crystal. Here, we extend this investigation to pillared layer MOFs with flexible side-chains, attached to the linker. Such functionalized (fu-)MOFs are experimen- tally known to have different properties with the side-chains acting as fixed guest molecules. First, in order to extend the parameterization for such flexible groups, 1a new parametrization strategy for MOF-FF had to be developed, using a multi- structure force based fit method. The resulting parametrization for a library of fu-MOFs is then validated with respect to a set of reference systems and shows very good accuracy. In the second step, a series of fu-MOFs with increasing side-chain length is studied with respect to the influence of the side-chains on the breathing behavior. For small supercells in PBC a systematic trend of the closed pore volume with the chain length is observed. However, for a nanocrystallite model a distinct interface between a closed and an open pore phase is visible only for the short chain length, whereas for longer chains the interface broadens and a nearly concerted trans- formation is observed. Only by molecular dynamics simulations using accurate force fields such complex phenomena can be studied on a molecular level.

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Modeling the Effects of O-sulfonation on the CID of Serine

10.26434/chemrxiv.11783628.v2 ◽

2020 ◽

Author(s):

Kenneth Lucas ◽

George Barnes

Keyword(s):

Sulfo Group ◽

High Energy ◽

Empirical Method ◽

Side Chain ◽

Energy Structure ◽

Direct Dynamics ◽

Theoretical Mass ◽

Intermolecular Proton Transfer ◽

Dynamics Simulations ◽

Semi Empirical

We present the results of direct dynamics simulations and DFT calculations aimed at elucidating the effect of \textit{O}-sulfonation on the collision induced dissociation for serine. Towards this end, direct dynamics simulations of both serine and sulfoserine were performed at multiple collision energies and theoretical mass spectra obtained. Comparisons to experimental results are favorable for both systems. Peaks related to the sulfo group are identified and the reaction dynamics explored. In particular, three significant peaks (m\z 106, 88, and 81) seen in the theoretical mass spectrum directly related to the sulfo group are analyzed as well as major peaks shared by both systems. Our analysis shows that the m\z 106 peaks result from intramolecular rearrangements, intermolecular proton transfer among complexes composed of initial fragmentation products, and at high energy side-chain fragmentation. The \mz 88 peak was found to contain multiple constitutional isomers, including a previously unconsidered, low energy structure. It was also seen that the RM1 semi empirical method was not able to obtain all of the major peaks seen in experiment for sulfoserine. In contrast, PM6 did obtain all major experimental peaks.

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Molecular Basis of Glucose Transport Mechanism in Plants

10.26434/chemrxiv.8049848.v1 ◽

2019 ◽

Cited By ~ 2

Author(s):

Balaji Selvam ◽

Ya-Chi Yu ◽

Liqing Chen ◽

Diwakar Shukla

Keyword(s):

Molecular Dynamics ◽

Free Energy ◽

Molecular Dynamics Simulations ◽

Conformational Changes ◽

Transport Mechanism ◽

Conformational Dynamics ◽

Site Directed Mutagenesis ◽

Free Energy Barrier ◽

Transport Cycle ◽

Dynamics Simulations

The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.

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