AtomicChargeCalculator: interactive web-based calculation of atomic charges in large biomolecular complexes and drug-like molecules

Ionescu, Crina-Maria; Sehnal, David; Falginella, Francesco Luca; Pant, Purbaj; Pravda, Lukáš; Bouchal, Tomáš; Vařeková, Radka Svobodová; Geidl, Stanislav; Koča, Jaroslav

doi:10.1186/s13321-015-0099-x

Cited by 58 publications

(50 citation statements)

References 86 publications

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“…Verstraelen et al have claimed that for the development of ab initio derived force fields, atomic charges must be computed from electronic structure computations, such that (i) they accurately describe the molecular electrostatic potential and (ii) they are transferable to the force field application of interest [130]. Ionescu and coworkers [190] argued that partial atomic charges are a well-established concept and are very useful in understanding and modeling the chemical reactivity behavior of molecules, ranging from simple compounds, to crystals, to large drug-like molecules, to biomacromolecular complexes with hundreds of thousands of atoms. Hamad et al [191] found that knowledge of atomic charges on specific systems is important, and that they are useful in gaining insight into metal-organic frameworks (MOFs).…”

Section: Is the Concept Of Atomic Charge Meaningful?mentioning

confidence: 99%

Halogen Bonding: A Halogen-Centered Noncovalent Interaction Yet to Be Understood

2019

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In addition to the underlying basic concepts and early recognition of halogen bonding, this paper reviews the conflicting views that consistently appear in the area of noncovalent interactions and the ability of covalently bonded halogen atoms in molecules to participate in noncovalent interactions that contribute to packing in the solid-state. It may be relatively straightforward to identify Type-II halogen bonding between atoms using the conceptual framework of σ-hole theory, especially when the interaction is linear and is formed between the axial positive region (σ-hole) on the halogen in one monomer and a negative site on a second interacting monomer. A σ-hole is an electron density deficient region on the halogen atom X opposite to the R–X covalent bond, where R is the remainder part of the molecule. However, it is not trivial to do so when secondary interactions are involved as the directionality of the interaction is significantly affected. We show, by providing some specific examples, that halogen bonds do not always follow the strict Type-II topology, and the occurrence of Type-I and -III halogen-centered contacts in crystals is very difficult to predict. In many instances, Type-I halogen-centered contacts appear simultaneously with Type-II halogen bonds. We employed the Independent Gradient Model, a recently proposed electron density approach for probing strong and weak interactions in molecular domains, to show that this is a very useful tool in unraveling the chemistry of halogen-assisted noncovalent interactions, especially in the weak bonding regime. Wherever possible, we have attempted to connect some of these results with those reported previously. Though useful for studying interactions of reasonable strength, IUPAC’s proposed “less than the sum of the van der Waals radii” criterion should not always be assumed as a necessary and sufficient feature to reveal weakly bound interactions, since in many crystals the attractive interaction happens to occur between the midpoint of a bond, or the junction region, and a positive or negative site.

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Section: Is the Concept Of Atomic Charge Meaningful?mentioning

confidence: 99%

Halogen Bonding: A Halogen-Centered Noncovalent Interaction Yet to Be Understood

2019

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“…In each iteration of stage I, the classical MD segment was started from the snapshot with the highest content of secondary structure sampled during the preceding segment of perturbed MD; if no suitable structure could be identified (i.e., no residues were involved in a secondary structure element), the last snapshot of the perturbed MD segment was used as a starting frame for the subsequent segment of classical MD. Before starting perturbed MD, the native charges from the topology file were replaced with non-native charges, which were computed using the Electronegativity Equalization Method 26 implemented in ACC 71 . In the ACC calculation, the total charge was +1 e, −1 e, and 0 e for the Trp-cage, Aβ17-34, and (AAQAA)3, respectively; no solvent was included in the ACC calculation; the parameter set EX-NPA_6-31Gd_PCM was used 27 , and the option Full EEM was chosen.…”

Section: Methodsmentioning

confidence: 99%

Charge-perturbation dynamics — a new avenue towards in silico protein folding

Pant

Ramos

Ionescu

et al. 2019

Preprint

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13Molecular dynamics (MD) has greatly contributed to understanding and predicting the way 14 proteins fold. However, the time-scale and complexity of folding are not accessible via 15 classical MD. Furthermore, efficient folding pipelines involving enhanced MD techniques 16 are not routinely accessible. We aimed to determine whether perturbing the electrostatic 17 component of the MD force field can help expedite folding simulations. We developed 18 charge-perturbation dynamics (CPD), an MD-based simulation approach that involves 19 periodically perturbing the atomic charges to values non-native to the MD force field. CPD 20 obtains suitable sampling via multiple iterations in which a classical MD segment (with 21 native charges) is followed by a very short segment of perturbed MD (using the same force 22 field and conditions, but with non-native charges); subsequently, partially folded 23 intermediates are refined via a longer segment of classical MD. Among the partially folded 24 structures from low-energy regions of the free-energy landscape sampled, the lowest-25 energy conformer with high root-mean-square deviation to the starting structure and low 26 radius of gyration is defined as the folded structure. Upon benchmark testing, we found 27 that medium-length peptides such as an alanine-based pentadecapeptide, an amyloid-β 28 peptide, and the tryptophan-cage mini-protein can fold starting from their extended linear 29 structure in under 45 ns of CPD (total simulation time), versus over 100 ns of classical 30 MD. CPD not only achieved folding close to the desired conformation but also sampled 31 key intermediates along the folding pathway without prior knowledge of the folding 32 mechanism or final folded structure. Our findings confirmed that perturbing the 33 electrostatic component of the classical MD force field can help expedite folding 34 3 simulations without changing the MD algorithm or using expensive computing 35 architectures. CPD can be employed to probe the folding dynamics of known, putative, or 36 planned peptides, as well as to improve sampling in more advanced simulations or to guide 37 further experiments. 38 39 4 Author summary 40 Folding represents the process by which proteins assemble into biologically active 41 conformations. While computational techniques such as molecular dynamics (MD) have 42 provided invaluable insight into protein folding, efficient folding pipelines are not 43 routinely accessible. In MD, the behavior of the studied molecule is simulated under the 44 concerted action of multiple forces described by mathematical functions employing 45 optimized parameters. Using non-native parameters effectively perturbs the MD force 46field. We show that this can be exploited to help expedite folding simulations. Specifically, 47we developed charge-perturbation dynamics (CPD), an MD-based simulation approach 48 that involves periodically perturbing the force field by using non-native atomic charges. 49For folding medium-length peptides such as the tryptophan-cage mini-protein s...

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“…The initial 3D quercetin conformation was determined using HyperChem 8.0 (Hypercube, Inc., Gainesville, FL, USA), and its charge was set to the most abundant anionic and fluorescent anion species at pH 7.4, taken from Dangles et al [37]. The quercetin partial charges were calculated according to Ionescu et al [53]. A grid map of size 80 × 80 × 80 Å was generated with a 0.375 Å spacing centered on the coordinates of the side-chain nitrogen in Trp214 in Sudlow's site I in subdomain IIA by the AutoGrid program [52], and then the Lamarckian genetic algorithm (LGA) [54] was applied.…”

Section: Docking Studiesmentioning

confidence: 99%

Indomethacin Increases Quercetin Affinity for Human Serum Albumin: A Combined Experimental and Computational Study and Its Broader Implications

Rimac

Tandarić

Vianello

et al. 2020

IJMS

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Human serum albumin (HSA) is the most abundant carrier protein in the human body. Competition for the same binding site between different ligands can lead to an increased active concentration or a faster elimination of one or both ligands. Indomethacin and quercetin both bind to the binding site located in the IIA subdomain. To determine the nature of the HSA-indomethacin-quercetin interactions, spectrofluorometric, docking, molecular dynamics studies, and quantum chemical calculations were performed. The results show that the indomethacin and quercetin binding sites do not overlap. Moreover, the presence of quercetin does not influence the binding constant and position of indomethacin in the pocket. However, binding of quercetin is much more favorable in the presence of indomethacin, with its position and interactions with HSA significantly changed. These results provide a new insight into drug-drug interactions, which can be important in situations when displacement from HSA or other proteins is undesirable or even desirable. This principle could also be used to deliberately prolong or shorten the xenobiotics’ half-life in the body, depending on the desired outcomes.

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AtomicChargeCalculator: interactive web-based calculation of atomic charges in large biomolecular complexes and drug-like molecules

Cited by 58 publications

References 86 publications

Halogen Bonding: A Halogen-Centered Noncovalent Interaction Yet to Be Understood

Halogen Bonding: A Halogen-Centered Noncovalent Interaction Yet to Be Understood

Charge-perturbation dynamics — a new avenue towards in silico protein folding

Indomethacin Increases Quercetin Affinity for Human Serum Albumin: A Combined Experimental and Computational Study and Its Broader Implications

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