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Binding Free Energy of Posaconazole in Two Protonation States to a Model of Captisol

posted May 17, 2019, 6:15 PM by Sheenam   [ updated May 19, 2019, 10:50 AM ]

Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients. However, its property as a weakly basic and poorly aqueous soluble drug results in poor bioavailability and variable absorption. Hence, for a better intravenous administration of the drug under aqueous conditions, the drug comes in a composition which consists of a solubilizing agent, a modified β-cyclodextrin such as Captisol which supposedly solubilizes with the drug in acidic medium. To test this hypothesis, we calculate the free binding energy of the drug Posaconazole to Captisol in different protonated states to understand the pH dependence of the observed solubility of posaconazole in the presence of Captisol via computational methods. The results of the computational experiments conducted here confirm the hypothesis that this effect is due to the higher affinity of the protonated form of Posaconazole relative to the unprotonated one.


Fig 1: Captisol-Posaconazole Complex (Posaconazole in Green)



Conformational Propensities of FXR Drug Inhibitors in Water Solution

posted May 7, 2019, 7:18 AM by Brenda Neuman   [ updated May 8, 2019, 5:59 AM ]

Hypercholesterolemia is a major cause of heart disease. A potential drug therapy for hypercholesterolemia is FXR inhibition because of the role of FXR receptors in bile acid and cholesterol metabolism. Drug molecules need to often reorganize conformations to bind protein receptors. The free energy penalty of reorganization is related to how often in solution the drug molecule adopts the same conformation as in the protein. By comparing the conformations of the FXR inhibitors in an aqueous environment to the conformation of these inhibitors in the enzyme substrate complex the probable effectiveness of the inhibitor as a drug can be determined. Different force fields were used to evaluate the distribution of conformations of two FXR inhibitors in an aqueous environment in order to analyze their reorganization penalty. The results from the different force fields were compared and it was determined that there was similarities and also significant differences between the conformations the different force fields produced and the reorganization penalties associated with them.

                                                                                            Figure 3. FXR inhibitor in Water Box


Research Poster that was presented at Brooklyn College Science Day on 05/03/19 can be viewed through the following link 

Heating and Cooling Strategy to Improve Estimates of CYFIP1p-Derived Peptides’ Helicity Probabilities in Biased Molecular Dynamics Simulations

posted Feb 24, 2019, 2:31 PM by Irene R   [ updated Feb 26, 2019, 6:32 PM ]

A CYFIP1p-derived peptide in VMD: bond lengths of 2.5 Å (units used by VMD) or less

for the middle three bonds would indicate a helical structure.



By Irene Rostovsky


Since the binding region of CYFIP1p can be used as a model for a precursor molecule for the development of a drug to treat Fragile X syndrome and cancer, we wanted to calculate the probability of finding the peptide corresponding to this binding region, and another peptide differing by one residue, in a helical conformation. Due to the difficulty of attaining convergence of random and helical starting conformations for one of our peptides, we performed a series of simulations at 6.25 kJ/mol bias force (previously determined as the optimal force by Megan Wang), where we manipulated temperatures in a manner that is similar conceptually to replica exchange, but is simpler to perform. We alternated between 400 K and 300 K for succeeding simulations to disturb the initial states and speed up exploration of different conformations. Our results so far suggest that alternating heating and cooling is an effective way to help peptides break out of their initial conformations, and form/ fully break alpha helices at a reasonable rate over 1 ms. The next step is to perform statistical analysis on our results and to test the possible convergence we have seen through our new heating/ cooling method.


Water energy contributions to structural inhomogeneity of curcubit[8]uril

posted Jun 15, 2018, 4:54 PM by Fatlum Hajredini   [ updated Jun 17, 2018, 7:09 AM ]

Expulsion of water from cavities on host binding sites can contribute a great deal of energy to binding of ligands. This can be attributed to the gain in entropy as the waters become unstructured. Accounting for such effects in binding free energy calculations greatly improves the prediction accuracy. This effect is likely to also contribute to the structural reorganization of macromolecules. Using molecular dynamics simulation and the recently developed SSTMap suite we investigate the contribution of water thermodynamics to the tendency of curcubit[8]uril to assuming a compacted structure. Hydration site analysis shows that structuring of waters at the cavity of cb8 carries an entropic penalty which was expected to be relieved upon compaction of cb8. A cb8ligand complex had overall more favorable hydration upon assuming a more compacted structure compared to its more extended counterpart, suggesting that the compaction was due to water expulsion. To investigate whether the same phenomenon would be observed in the cb8 complex alone, simulations were carried in an explicit solvation model, and an implicit solvation model which lacks water structure information. Contrary to expectation, when simulated in the implicit solvation model cb8 is predominantly compacted, and also assumes an overall more compact structure compared to any of the conformations in the explicit water simulation. Simulations in explicit solvent show a wide distribution of states, with the extended conformation being much more populated then the counterpart in the implicit solvent simulation. Taken together, these findings suggest that structural networks of water, when treated explicitly can have a significant impact on the structural reorganization of macromolecules. 


                    State Distribution of cb8 when simulated in implicit solvent (blue), or explicit solvent (red) as determined by differences in their radii of gyration. 

Tripeptide Stabilized Nanoemulsions for Cancer Therapy

posted May 24, 2018, 9:18 PM by Marium

A carboplatin derivative consisting of two oleic acids attached to a platinum head, used to kill cancer cells, is investigated in this project through chemical simulation software. One of the challenges of this class of anticancerous drugs is its high level of toxicity to the human body, which results in low clinical dosings of the drug and ultimately ineffective therapy. Thus, for drug delivery to the human body, the carboplatin derivative requires an emulsifier to stabilize it and shield its toxic agents. The emulsifiers used in this project are tripeptides because of their biodegradability and it has been shown that they are promising self assembly candidates in a previous study. In the first phase of this project, general features of oleic acid aggregates in water solution are investigated. In the second, tripeptides, specifically KYF (Lysine- Tyrosine - Phenylalanine) and DFF (Aspartic Acid- Diphenylalanine), are added to these aggregates in order to study the tripeptide stabilized nanoemulsions. The simulations gave insight about the interactions present in the nanoemulsions. 
Structure of KYF and oleic acid aggregate
Structure of KYF(green) and oleic acid aggregate
(carbons are gray, carboxyl groups are in red, amine groups are in blue)


Use of Umbrella Sampling Methods to Estimate Probability of CYFIP1p Helical Conformation

posted May 20, 2018, 11:58 AM by Megan Wang

Previously, we made modifications to the wild-type CYFIP1p to stabilize its α-helical structure and increase its binding efficiency to EIF4E. In this study, we utilized umbrella sampling methods to accelerate the sampling of possible peptide conformations, such that the probability of these conformations could be readily calculated from an MD simulation that would otherwise have taken months to collect a sufficient number of relevant samples. Using two Python scripts, we were able to apply a bias force onto CYFIP1p and measure the proportion of instances that CYFIP1p maintained a helical conformation. We effectively estimated the probability of such an outcome to be 0.18 percent if the bias force were nonexistent.

Potential bias force applied to interacting atoms in molecular system.  

Research Report

Possible Computational Evidence for Enhanced α-Helix in Modified CYFIP1-derived Peptides

posted Dec 7, 2017, 11:03 AM by Megan Wang   [ updated Mar 17, 2018, 9:29 PM by Emilio Gallicchio ]


Dysregulation of the eukaryotic translation initiation factor (eIf4E) has been shown to exist in Fragile X Syndrome, a leading cause of intellectual disabilities such as autism. The cytoplasmic FMRP-interacting protein 1 (CYFIP1) plays a key regulatory role in repressing associated mRNA translation by binding to eIF4E. A crucial secondary structure element in the interactions between a CYFIP1-derived peptide (CYFIP1p) and eIF4E is the α-helix, and as a consequence, improving the persistence of α-helicity of the peptide could lead to improved binding efficiency. In our study, we made computer-aided chemical modifications in an effort to further stabilize the α-helix structures of peptides derived from wild-type CYFIP1p. Our findings suggest the addition of a staple comprised of alkyls or an aromatic ring has no significant impact on the secondary structure elements of the CYFIP1-derived peptides. However, modifications comprised of a long chemical staple combined with a mutation from serine to alanine resulted in improved α-helix stability and thus, exhibited a potential for enhanced binding efficiency. 

Snapshot of the trajectory for a CYFIP1-derived peptide exhibiting α-helix fold. 



Gaussian-based Volume and Surface Area algorithm for GPUs

posted Jan 8, 2017, 9:26 AM by Emilio Gallicchio   [ updated Jun 5, 2018, 11:07 AM ]


The model proposed by Grant & Pickup [J. Phys. Chem. 99, 3503-3510 (1995)] is a well-established method to estimate accurately volume and surface areas of molecules. The method is based on the inclusion-exclusion formula of statistical physics (also known as the Poincaré formula). It states that the volume of an object composed of multiple overlapping bodies is given by the sum of the volumes of the bodies, minus the sum of the overlap volumes between pairs of bodies, plus the sum of the overlap volumes between triplets of bodies, and so on:
Atomic volumes are represented by Gaussian densities and overlap volumes are computed using standard Gaussian overlap integrals. The model is fully analytic. For example, the solvent-accessible surface area of an atom is obtained as the derivative of the molecular volume with respect to the atomic radius of an atom.

The model leads to a tree-based algorithm in which overlap volumes are recursively evaluated. 
overlap tree
We have used this model extensively to implement the non-polar component and the self-adjusting pair-wise descreening method for the Generalized Born solvation electrostatic component of the of the AGBNP solvation model. Our CPU implementation is based on a dept-first traversal of the tree.

Lately we have been working on a GPU implementation of the Gaussian volumetric model. As one can imagine, tree-based recursive algorithms do not easily lend themselves to GPUs. However, we finally found an efficient solution based on a flat arrays representation of the tree and breadth-first traversal (see paper in JCC).
GPU tree traversal
The resulting GPU implementation is 50 to 100 times faster than our best CPU implementation. With the help with the development team at Stanford, the algorithm is now available as a plugin of the OpenMM molecular mechanics package.





Dopamine D3 receptor antagonists

posted Oct 31, 2016, 1:16 PM by Pierpaolo Cordone   [ updated Feb 1, 2018, 9:10 PM by Emilio Gallicchio ]

According to Newman et al., in all D3 receptor antagonists a salt bridge between the protonated amine in the primary pharmcophore and Asp 110 is observed. Previous antagonists candidates having a stepholidine ring as a primary pharmacophore have been synthetized in our lab. The protonated nitrogen of the pharmacophore makes the same interaction with Asp 110 observed in Newman et al.10 Some of the molecules used in this study like 216F (figure 4 left) have the same feature. However, molecules like 217F don't do the same interaction (figure 4 right). In order to find out the reason why those molecules interact differently 216F and 217F were superimposed (figure 5). From the superimposition it looks that there is electronic repulsion between a cyano group in para of the aromatic ring and the carbonyl of Val 189. This repulsion would cause the molecule to rearrange in another way in order to fit in the receptor. This rearrangement would prevent the protonated amine of 217F to make the salt bridge with Asp 110 in the primary binding site (OBS). This phenomenon occurs in all molecules with a substitution in para.

Figure 4. left, SG-216F makes the salt bridge with Asp 110. Righ, SG-217F does not make the salt bridge interaction with Asp 110. 

Figure 5. SG-216F in blue and SG-217F in pink. SG-217F cannot make the salt bridge interaction because of the clash between the cyano group and valine 189.

Prediction of Binding Energy affinities of Cucurbituril clip(host) with various guests as a part of SAMPL5 Challenge

posted Apr 5, 2016, 8:15 PM by Divya Kaur

By: Divya K.Matta
 Ph.D student in Chemistry

The binding energies of Cucurbituril clip with various guests have been calculated using Binding energy distribution Analysis Method(BEDAM). The method employs AGBNP2(Analytic Generalized Born Plus NonPolar2) as an implicit(continuum) solvation model. Molecular Dynamic(MD) simulations were carried out to predict the binding free energies of these host-guest systems. Cucurbituril clip is deprotonated and has a charge of -4 due to the presence of four sulfonate groups.The values of Binding energies of these host guests system depends on the number of factors such as the strength of interactions between them, for example, depending upon whether they have hydrogen bonding, electrostatic or hydrophobic interactions, the binding energies vary accordingly. Also, it depends on the charge of guests molecules whether they are neutral or ionised.With the guidance of Prof.Emilio, I learnt the BEDAM methodology and its applications on host-guest systems. 


Image :Interaction of Cucurbituril clip(host) with the guest 

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