Parameterization of electrostatic interactions for molecular dynamics simulations of heterocyclic polymers

2015 ◽  
Vol 53 (13) ◽  
pp. 912-923 ◽  
Author(s):  
Victor M. Nazarychev ◽  
Sergey V. Larin ◽  
Alexander V. Yakimansky ◽  
Natalia V. Lukasheva ◽  
Andrey A. Gurtovenko ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Heterocyclic Polymers ◽  
Dynamics Simulations

scholarly journals SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

2019 ◽  
Vol 24 (9) ◽  
pp. 928-938 ◽  
Author(s):  
Luca Palazzolo ◽  
Chiara Paravicini ◽  
Tommaso Laurenzi ◽  
Sara Adobati ◽  
Simona Saporiti ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Amino Acid Residues ◽  
Dibasic Amino Acid ◽  
Novel Target ◽  
Function Relationship ◽  
Dynamics Simulations

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane α-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure–function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport.

scholarly journals Effect of Ca2+ on the promiscuous target-protein binding mechanism of calmodulin

2018 ◽  
Author(s):  
Annie M. Westerlund ◽  
Lucie Delemotte
Keyword(s):  
Molecular Dynamics ◽  
Protein Binding ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Solvent Exposure ◽  
Conformational States ◽  
Hydrophobic Residues ◽  
Target Proteins ◽  
Flexible Mechanism ◽  
Dynamics Simulations

AbstractCalmodulin (CaM) is a calcium sensing protein that regulates the function of a large number of proteins, thus playing a crucial part in many cell signaling path- ways. CaM has the ability to bind more than 300 different target peptides in a Ca2+-dependent manner, mainly through the exposure of hydrophobic residues. How CaM can bind a large number of targets while retaining some selectivity is a fascinating open question.Here, we explore the mechanism of CaM selective promiscuity for selected target proteins. Analyzing enhanced sampling molecular dynamics simulations of Ca2+-bound and Ca2+-free CaM via spectral clustering has allowed us to identify distinct conformational states, characterized by interhelical angles, secondary structure determinants and the solvent exposure of specific residues. We searched for indicators of conformational selection by mapping solvent exposure of residues in these conformational states to contacts in structures of CaM/target peptide complexes. We thereby identified CaM states involved in various binding classes arranged along a depth binding gradient. Binding Ca2+ modifies the accessible hydrophobic surface of the two lobes and allows for deeper binding. Apo CaM indeed shows shallow binding involving predominantly polar and charged residues. Furthermore, binding to the C-terminal lobe of CaM appears selective and involves specific conformational states that can facilitate deep binding to target proteins, while binding to the N-terminal lobe appears to happen through a more flexible mechanism. Thus the long-ranged electrostatic interactions of the charged residues of the N-terminal lobe of CaM may initiate binding, while the short-ranged interactions of hydrophobic residues in the C-terminal lobe of CaM may account for selectivity.This work furthers our understanding of the mechanism of CaM binding and selectivity to different target proteins and paves the way towards a comprehensive model of CaM selectivity.Author summaryCalmodulin is a protein involved in the regulation of a variety of cell signaling pathways. It acts by making usually calcium-insensitive proteins sensitive to changes in the calcium concentration inside the cell. Its two lobes bind calcium and allow the energetically unfavorable exposure of hydrophobic residues to the aqueous environment which can then bind target proteins. The mechanisms behind the simultaneous specificity and variation of target protein binding is yet unknown but will aid understanding of the calcium-signaling and regulation that occur in many of our cellular processes.Here, we used molecular dynamics simulations and data analysis techniques to investigate what effect calcium has on the binding modes of calmodulin. The simulations and analyses allow us to observe and differentiate specific states. One domain of calmodulin is shown to be selective with binding involving short- distance interactions between hydrophobic residues, while the other binds target proteins through a more flexible mechanism involving long-distance electrostatic interactions.

scholarly journals Adsorption of Fibronectin Fragment on Surfaces Using Fully Atomistic Molecular Dynamics Simulations

2018 ◽  
Vol 19 (11) ◽  
pp. 3321 ◽  
Author(s):  
Evangelos Liamas ◽  
Karina Kubiak-Ossowska ◽  
Richard Black ◽  
Owen Thomas ◽  
Zhenyu Zhang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Charged Surface ◽  
Cell Binding ◽  
Binding Region ◽  
Charged Surfaces ◽  
Fibronectin Fragment ◽  
Dynamics Simulations ◽  
Positively Charged

The effect of surface chemistry on the adsorption characteristics of a fibronectin fragment (FNIII8–10) was investigated using fully atomistic molecular dynamics simulations. Model surfaces were constructed to replicate self-assembled monolayers terminated with methyl, hydroxyl, amine, and carboxyl moieties. It was found that adsorption of FNIII8–10 on charged surfaces is rapid, specific, and driven by electrostatic interactions, and that the anchoring residues are either polar uncharged or of opposing charge to that of the targeted surfaces. On charged surfaces the presence of a strongly bound layer of water molecules and ions hinders FNIII8–10 adsorption. In contrast, adsorption kinetics on uncharged surfaces are slow and non-specific, as they are driven by van der Waals interactions, and the anchoring residues are polar uncharged. Due to existence of a positively charged area around its cell-binding region, FNIII8–10 is available for subsequent cell binding when adsorbed on a positively charged surface, but not when adsorbed on a negatively charged surface. On uncharged surfaces, the availability of the fibronectin fragment’s cell-binding region is not clearly distinguished because adsorption is much less specific.

scholarly journals Charge Interactions in a Highly Charge-depleted Protein

2020 ◽  
Author(s):  
Stefan Hervø-Hansen ◽  
Casper Højgaard ◽  
Kristoffer Enøe Johansson ◽  
Yong Wang ◽  
Khadija Wahni ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Nmr Spectroscopy ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Protein Electrostatics ◽  
Surface Charges ◽  
Constant Ph ◽  
Charged Residues ◽  
Dynamics Simulations ◽  
Constant Ph Molecular Dynamics

ABSTRACTInteractions between charged residues are difficult to study because of the complex network of interactions found in most proteins. We have designed a purposely simple system to investigate this problem by systematically introducing individual and pairs of charged and titratable residues in a protein otherwise free of such residues. We used constant pH molecular dynamics simulations, NMR spectroscopy, and thermodynamic double mutant cycles to probe the structure and energetics of the interaction between the charged residues. We found that the partial burial of surface charges contributes to a shift in pKa value, causing an aspartate to titrate in the neutral pH range. Additionally, the interaction between pairs of residues was found to be highly context dependent, with some pairs having no apparent preferential interaction, while other pairs would engage in coupled titration forming a highly stabilized salt bridge. We find good agreement between experiments and simulations, and use the simulations to rationalize our observations and to provide a detailed mechanistic understanding of the electrostatic interactions.SignificanceElectrostatic forces are important for protein folding and are favored targets of protein engineering. However, despite the many advances in the field of protein electrostatics, the prediction of changes in protein structure and function upon introduction or removal of titratable residues is still complicated. In order to provide a basic understanding of protein electrostatics we here characterize a highly charge-depleted protein and its titratable variants by a combination of NMR spectroscopy and constant pH molecular dynamics simulations. Our investigations reveal how strongly interacting residues engaged in salt bridging, can be characterized. Furthermore, our study may also enrich and facilitate the understanding of dehydration of salt-bridges and its potential effect on protein stability.

scholarly journals Strong reduction of the chain rigidity of hyaluronan by selective binding of Ca2+ ions

2020 ◽  
Author(s):  
G. Giubertoni ◽  
A. Pérez de Alba Ortíz ◽  
F. Bano ◽  
X. Zhang ◽  
R.J. Linhardt ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Structural Changes ◽  
Polymer Chains ◽  
Single Chain ◽  
Molecular Hydrogen Bond ◽  
Dynamics Simulations ◽  
Chain Force ◽  
Molecular Picture

ABSTRACTThe biological functions of natural polyelectrolytes are strongly influenced by the presence of ions, which bind to the polymer chains and thereby modify their properties. Although the biological impact of such modifications is well-recognized, a detailed molecular picture of the binding process and of the mechanisms that drive the subsequent structural changes in the polymer is lacking. Here, we study the molecular mechanism of the condensation of calcium, a divalent cation, on hyaluronan, a ubiquitous polymer in human tissues. By combining two-dimensional infrared spectroscopy experiments with molecular dynamics simulations, we find that calcium specifically binds to hyaluronan at millimolar concentrations. Because of its large size and charge, the calcium cation can bind simultaneously to the negatively charged carboxylate group and the amide group of adjacent saccharide units. Molecular dynamics simulations and single-chain force spectroscopy measurements provide evidence that the binding of the calcium ions weakens the intra-molecular hydrogen-bond network of hyaluronan, increasing the flexibility of the polymer chain. We also observe that the binding of calcium to hyaluronan saturates at a maximum binding fraction of ~10-15 mol %. This saturation indicates that the binding of Ca2+ strongly reduces the probability of subsequent binding of Ca2+ at neighboring binding sites, possibly as a result of enhanced conformational fluctuations and/or electrostatic repulsion effects. Our findings provide a detailed molecular picture of ion condensation, and reveal the severe effect of a few, selective and localized electrostatic interactions on the rigidity of a polyelectrolyte chain.TOC

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