Implicit treatment of solvent dispersion forces in protein simulations

Hassan, Sergio A.

doi:10.1002/jcc.23655

Cited by 12 publications

(24 citation statements)

References 54 publications

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“…The study builds upon a series of recent developments on ab initio complex structure prediction [21, 22] and force field optimization [23–25]. The predicted binding modes suggest that p5 is a non-selective competitive inhibitor of p25, in accordance with available experimental data.…”

Section: Introductionmentioning

confidence: 68%

“…Replicas are distributed over temperatures in ascending order of energies, with the lowest energy assigned to the lowest temperature where data are collected (here, 37 °C). Simulations are carried out with the all-atom CHARMM force field [30] and the SCP implicit solvent model [23, 25, 31, 32]. The converged canonical distribution contains a large number of structures, which are clustered to obtain a discrete set of conformational families [22].…”

Section: Resultsmentioning

confidence: 99%

“…The resulting canonical distribution obtained upon convergence is post-processed by the clustering algorithm to identify a discrete set of binding modes using a cutoff of 2 Å. Simulations are carried out with the all-atom CHARMM force field [30] and the SCP implicit solvent model [23, 25, 31, 32]. The distributions of first-encounter modes (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore

Cardone

Brady

Sriram

et al. 2016

J Comput Aided Mol Des

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The hyperactivity of the cyclic dependent kinase 5 (CDK5) induced by the activator protein p25 has been linked to a number of pathologies of the brain. The CDK5-p25 complex has thus emerged as a major therapeutic target for Alzheimer’s disease (AD) and other neurodegenerative conditions. Experiments have shown that the peptide p5 reduces the CDK5-p25 activity without affecting the endogenous CDK5-p35 activity, whereas the peptide TFP5, obtained from p5, elicits similar inhibition, crosses the blood-brain barrier, and exhibits behavioral rescue of AD mice models with no toxic side effects. The molecular basis of the kinase inhibition is not currently known, and is here investigated by computer simulations. It is shown that p5 binds the kinase at the same CDK5/p25 and CDK5/p35 interfaces, and is thus a non-selective competitor of both activators, in agreement with available experimental data in vitro. Binding of p5 is enthalpically driven with an affinity estimated in the low μM range. A quantitative description of the binding site and pharmacophore is presented, and options are discussed to increase the binding affinity and selectivity in the design of drug-like compounds.

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Section: Introductionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore

Cardone

Brady

Sriram

et al. 2016

J Comput Aided Mol Des

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“…The effects of water are described by the screened Coulomb potentials (SCP) implicit solvent model . In this model, the total nonbonded energy of a hydrated solute composed of N atoms is given by

E = \frac{1}{2} \sum_{i \neq j}^{N} \frac{q_{i} q_{j}}{r_{i j} D_{i j} (r_{i j}; r)} + \frac{1}{2} \sum_{i = 1}^{N} \frac{q_{i}^{2}}{R_{i} (q_{i}; r)} true{\frac{1}{D_{i} [R_{i} (q_{i}; r); r]} - 1 true} + E_{v d w}^{0} - \sum_{i \neq j}^{N} ε_{i j} (r) {(σ_{i j} / r_{i j})}^{6} + a γ (r)

where r ≡ { r 1 , r 2 ,…, r N } represents the conformation of the solute, r i is the position of atom i , and r ij is the distance between atoms i and j .…”

Section: Atomistic Representation Of the Solute And Implicit Represenmentioning

confidence: 99%

Detection and characterization of nonspecific, sparsely populated binding modes in the early stages of complexation

et al. 2015

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A method is proposed to study protein-ligand binding in a system governed by specific and non-specific interactions. Strong associations lead to narrow distributions in the proteins configuration space; weak and ultra-weak associations lead instead to broader distributions, a manifestation of non-specific, sparsely-populated binding modes with multiple interfaces. The method is based on the notion that a discrete set of preferential first-encounter modes are metastable states from which stable (pre-relaxation) complexes at equilibrium evolve. The method can be used to explore alternative pathways of complexation with statistical significance and can be integrated into a general algorithm to study protein interaction networks. The method is applied to a peptide-protein complex. The peptide adopts several low-population conformers and binds in a variety of modes with a broad range of affinities. The system is thus well suited to analyze general features of binding, including conformational selection, multiplicity of binding modes, and nonspecific interactions, and to illustrate how the method can be applied to study these problems systematically. The equilibrium distributions can be used to generate biasing functions for simulations of multiprotein systems from which bulk thermodynamic quantities can be calculated.

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“…The parameters ε i,j in eq 5 are determined by heating the coarse dimer, using a single ε alb for all ε i,j and σ i,j = ( σ i + σ j )/2. Assuming a vdW contribution on the order of kT (dispersion makes relatively small contributions to protein–protein interaction in water 34,35 ), the calculations yield ε alb ~ 0.1 kcal mol −1 .…”

Section: Model and Simulations Setupmentioning

confidence: 99%

Role of Albumin in the Formation and Stabilization of Nanoparticle Aggregates in Serum Studied by Continuous Photon Correlation Spectroscopy and Multiscale Computer Simulations

et al. 2014

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Recently, small (<5 nm diameter) nanoparticles (NPs) have shown improved in vivo biocompatibility compared to that of larger (>10 nm) NPs. However, the fate of small NPs under physiological conditions is poorly understood and remains unexplored. Here, the long-term aggregation behavior of gold nanoparticles (AuNPs) exposed to serum proteins in a near-physiological setup is studied using continuous photon correlation spectroscopy and computer simulations. It is found that the medium, temperature, and NP concentration affect the aggregation of AuNPs, but the observed aggregates are much smaller than previously reported. Simulations show that a single layer of albumin is deposited on the NP surface, but the properties of the aggregates (size, shape, and internal structure) depend critically on the charge distribution on the proteins, which changes with the conditions of the solution. These results explain the seemingly conflicting data reported in the literature regarding the size of aggregates and the morphology of the albumin corona. The simulations suggest that controlling the concentration of NPs as well as the pH and ionic strength of the solution prior to intravenous administration may help to preserve properties of the functionalized NPs in the bloodstream.

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Implicit treatment of solvent dispersion forces in protein simulations

Cited by 12 publications

References 54 publications

Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore

Computational study of the inhibitory mechanism of the kinase CDK5 hyperactivity by peptide p5 and derivation of a pharmacophore

Detection and characterization of nonspecific, sparsely populated binding modes in the early stages of complexation

Role of Albumin in the Formation and Stabilization of Nanoparticle Aggregates in Serum Studied by Continuous Photon Correlation Spectroscopy and Multiscale Computer Simulations

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