Effect of available volumes on radial distribution functions

Astley, Timothy; Birch, G. G.; Drew, Michael G. B.; Rodger, P. Mark; Wilden, Gareth R. H.

doi:10.1002/(sici)1096-987x(199802)19:3<363::aid-jcc9>3.0.co;2-r

Cited by 30 publications

(24 citation statements)

References 11 publications

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“…The calculation of accessible volume around the peptide has been carried out by using a Monte Carlo random number insertion method. 72 The results corresponding to the repeat units R1− R7 as obtained by averaging over eight different peptide monomer conformations (S1−S8) are depicted in Figure 7a.…”

Section: Resultsmentioning

confidence: 99%

“…In this calculation, we have considered the actual volume accessible to water within a spherical shell of radius r and thickness δr around the peptide residues, instead of the entire volume of the shell to normalize the g ( r ) values. The calculation of accessible volume around the peptide has been carried out by using a Monte Carlo random number insertion method . The results corresponding to the repeat units R1–R7 as obtained by averaging over eight different peptide monomer conformations (S1–S8) are depicted in Figure a.…”

Section: Results and Discussionmentioning

confidence: 99%

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Importance of Solvent in Guiding the Conformational Properties of an Intrinsically Disordered Peptide

Mondal

Bandyopadhyay

2021

Langmuir

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Aggregated form of α-synuclein in the brain has been found to be the major component of Lewy bodies that are hallmarks of Parkinson′s disease (PD), the second most devastating neurodegenerative disorder. We have carried out room-temperature all-atom molecular dynamics (MD) simulations of an ensemble of widely different α-synuclein1–95 peptide monomer conformations in aqueous solution. Attempts have been made to obtain a generic understanding of the local conformational motions of different repeat unit segments, namely R1–R7, of the peptide and the correlated properties of the solvent at the interface. The analyses revealed relatively greater rigidity of the hydrophobic R6 unit as compared to the other repeat units of the peptide. Besides, water molecules around R6 have been found to be less structured and weakly interacting with the peptide. These are important observations as the R6 unit with reduced conformational motions can act as the nucleation site for the aggregation process, while less structured weakly interacting water around it can become displaced easily, thereby facilitating the hydrophobic collapse of the peptide monomers and their association during the nucleation phase at higher concentrations. In addition, we demonstrated presence of doubly coordinated highly ordered as well as triply coordinated relatively disordered water molecules at the interface. We believe that while the ordered water molecules can favor water-mediated interactions between different peptide monomers, the randomly ordered ones on the other hand are likely to be expelled easily from the interface, thereby facilitating direct peptide–peptide interactions during the aggregation process.

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Section: Resultsmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Importance of Solvent in Guiding the Conformational Properties of an Intrinsically Disordered Peptide

Mondal

Bandyopadhyay

2021

Langmuir

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“…In addition, the s ( r ) values are normalized by using the actual volume available to water within a shell at a distance r with thickness δr instead of by the entire volume of the corresponding spherical shell, as usually done in standard radial distribution function (rdf) calculations. We have employed the method proposed by Astley et al to calculate the available volume of water around the peptide surfaces. s ( r ) may be regarded as the surface distribution function of waters, as the employed minimum distance criteria measures the distance of waters from microscopically ragged peptide surfaces.…”

Section: Resultsmentioning

confidence: 99%

Interfacial Water Arrangement in the Ice-Bound State of an Antifreeze Protein: A Molecular Dynamics Simulation Study

Midya

Bandyopadhyay

2017

Langmuir

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Molecular dynamics (MD) simulations have been carried out to study the heterogeneous ice nucleation on modeled peptide surfaces. Simulations show that large peptide surfaces made by TxT (threonine-x-threonine) motifs with the arrangements of threonine (Thr) residues identical to the periodic arrangements of waters on either the basal or prism plane of ice are capable of ice nucleation. Nucleated ice plane is the (0001) basal plane of hexagonal ice (Ih) or (111) plane of cubic ice (Ic). However, due to predefined simulation cell dimensions, the ice growth is only observed on the surface where the Thr residues are arranged like the water arrangement on the basal plane of ice Ih. The γ-methyl and γ-hydroxyl groups of Thr residue are necessary for such ice formation. From this ice nucleation and growth simulation, the interfacial water arrangement in the ice-bound state of Tenebrio molitor antifreeze protein (TmAFP) has been determined. The interfacial water arrangement in the ice-bound state of TmAFP is characterized by five-membered hydrogen bonded rings, where each of the hydroxyl groups of the Thr residues on the ice-binding surface (IBS) of the protein is a ring member. It is found that the water arrangement at the protein-ice interface is distorted from that in bulk ice. Our analysis further reveals that the hydroxyl groups of Thr residues on the IBS of TmAFP form maximum three hydrogen bonds each with the waters in the bound state and methyl groups of Thr residues occupy wider spaces than the normal grooves on the (111) plane of ice Ic. Methyl groups are also located above and along the 3-fold rotational axes of the chair-formed hexagonal hydrogen bonded water rings on the (111) plane.

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“…The reasoning behind this is that not all of the volume around a ligand atom j is actually available to a protein atom i , as protein atoms cannot occupy space already taken by ligand atoms. The effect of excluded volume on RDFs has previously been recognized in a molecular dynamics study of monosaccharides in water 28. For the calculation of the expected number of contacts in statistical potentials, one should only use the available volume, instead of the full volume of a spherical shell.…”

Section: Introductionmentioning

confidence: 99%

General and targeted statistical potentials for protein–ligand interactions

Mooij¹,

Verdonk²

2005

Proteins

326

263

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We present a novel atom-atom potential derived from a database of protein-ligand complexes. First, we clarify the similarities and differences between two statistical potentials described in the literature, PMF and Drugscore. We highlight shortcomings caused by an important factor unaccounted for in their reference states, and describe a new potential, which we name the Astex Statistical Potential (ASP). ASP's reference state considers the difference in exposure of protein atom types towards ligand binding sites. We show that this new potential predicts binding affinities with an accuracy similar to that of Goldscore and Chemscore. We investigate the influence of the choice of reference state by constructing two additional statistical potentials that differ from ASP only in this respect. The reference states in these two potentials are defined along the lines of Drugscore and PMF. In docking experiments, the potential using the new reference state proposed for ASP gives better success rates than when these literature reference states were used; a success rate similar to the established scoring functions Goldscore and Chemscore is achieved with ASP. This is the case both for a large, general validation set of protein-ligand structures and for small test sets of actives against four pharmaceutically relevant targets. Virtual screening experiments for these targets show less discrimination between the different reference states in terms of enrichment. In addition, we describe how statistical potentials can be used in the construction of targeted scoring functions. Examples are given for cdk2, using four different targeted scoring functions, biased towards increasingly large target-specific databases. Using these targeted scoring functions, docking success rates as well as enrichments are significantly better than for the general ASP scoring function. Results improve with the number of structures used in the construction of the target scoring functions, thus illustrating that these targeted ASP potentials can be continuously improved as new structural data become available.

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Effect of available volumes on radial distribution functions

Cited by 30 publications

References 11 publications

Importance of Solvent in Guiding the Conformational Properties of an Intrinsically Disordered Peptide

Importance of Solvent in Guiding the Conformational Properties of an Intrinsically Disordered Peptide

Interfacial Water Arrangement in the Ice-Bound State of an Antifreeze Protein: A Molecular Dynamics Simulation Study

General and targeted statistical potentials for protein–ligand interactions

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