Kirkwood-Buff-Derived Force Field for Peptides and Proteins: Philosophy and Development of KBFF20.

A new classical nonpolarizable force field, KBFF20, for the simulation of peptides and proteins is presented. The force field relies heavily on the use of Kirkwood-Buff theory to provide a comparison of simulated and experimental Kirkwood-Buff integrals for solutes containing the functional groups common in proteins, thus ensuring intermolecular interactions that provide a good balance between the peptide-peptide, peptide-solvent, and solvent-solvent distributions observed in solution mixtures. In this way, it differs significantly from other biomolecular force fields.

Interaction of Camptothecin with Model Cellular Membranes.

Accurate and efficient prediction of drug partitioning in model membranes is of significant interest to the pharmaceutical industry. Herein, we utilize advanced sampling methods, specifically, the adaptive biasing force methodology to calculate the potential of mean force for a model hydrophobic anticancer drug, camptothecin (CPT), across three model interfaces. We consider an octanol bilayer, a thick octanol/water interface, and a model 1-palmitoyl-2-oleoyl--glycero-3-phosphocholine (POPC)/water interface.

Rational Coarse-Grained Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes.

Peptide self-assembly has been used to design an array of nanostructures that possess functional biomedical applications. Experimental studies have reported nanofilament and nanotube formation from peptide-based drug amphiphiles (DAs). These DAs have shown to possess an inherently high drug loading with a tunable release mechanism.

Molecular Mechanism for the Role of the H2A and H2B Histone Tails in Nucleosome Repositioning.

The nucleosome core particle (NCP) is the basic packaging unit of DNA. Recently reported structures of the NCP suggest that the histone octamer undergoes conformational changes during the process of DNA translocation around the histone octamer. Herein, we demonstrate with long-time all-atomistic molecular dynamics simulations that the histone tails play a critical role in this nucleosome repositioning.

Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes.

We report here on long-time all-atomistic molecular dynamics simulations of functional supramolecular nanotubes composed by the self-assembly of peptide-drug amphiphiles (DAs). These DAs have been shown to possess an inherently high drug loading of the hydrophobic anticancer drug camptothecin. We probe the self-assembly mechanism from random with ∼0.

Effect of Nucleotide State on the Protofilament Conformation of Tubulin Octamers.

At the molecular level, the dynamic instability (random growth and shrinkage) of the microtubule (MT) is driven by the nucleotide state (GTP vs GDP) in the β subunit of the tubulin dimers at the MT cap. Here, we use large-scale molecular dynamics (MD) simulations and normal-mode analysis (NMA) to characterize the effect of a single GTP cap layer on tubulin octamers composed of two neighboring protofilaments (PFs). We utilize recently reported high-resolution structures of dynamic MTs to simulate a GDP octamer both with and without a single GTP cap layer.

Isomeric control of the mechanical properties of supramolecular filament hydrogels.

Supramolecular filament hydrogels are an emerging class of biomaterials that hold great promise for regenerative medicine, tissue engineering, and drug delivery. However, fine-tuning of their bulk mechanical properties at the molecular level without altering their network structures remains a significant challenge. Here we report an isomeric strategy to construct amphiphilic peptides through the conjugation of isomeric hydrocarbons to influence the local viscoelastic properties of their resulting supramolecular hydrogels.

Coarse-grained molecular dynamics studies of the structure and stability of peptide-based drug amphiphile filaments.

Peptide-based supramolecular filaments, in particular filaments self-assembled by drug amphiphiles (DAs), possess great potential in the field of drug delivery. These filaments possess one hundred percent drug loading, with a release mechanism that can be tuned based on the dissociation of the supramolecular filaments and the degradation of the DAs [Cheetham et al., J.

Molecular simulations of peptide amphiphiles.

This review describes recent progress in the area of molecular simulations of peptide assemblies, including peptide-amphiphiles and drug-amphiphiles. The ability to predict the structure and stability of peptide self-assemblies from the molecular level up is vital to the field of nanobiotechnology. Computational methods such as molecular dynamics offer the opportunity to characterize intermolecular forces between peptide-amphiphiles that are critical to the self-assembly process.

- Stacking Mediated Chirality in Functional Supramolecular Filaments.

While a great diversity of peptide-based supra-molecular filaments have been reported, the impact of an auxiliary segment on the chiral assembly of peptides remains poorly understood. Herein we report on the formation of chiral filaments by the self-assembly of a peptide-drug conjugate containing an aromatic drug camptothecin (CPT) in a computational study. We find that the chirality of the filament is mediated by the ‒ stacking between CPTs, not only by the well-expected intermolecular hydrogen bonding between peptide segments.

Molecular simulation of the concentration-dependent interaction of hydrophobic drugs with model cellular membranes.

We report here the interactions between a hydrophobic drug and a model cellular membrane at the molecular level using all-atom molecular dynamics simulations of paclitaxel, a hydrophobic cancer drug. The calculated free energy of a single drug across the bilayer interface displays a minimum in the outer hydrophobic zone of the membrane. The transfer free energy shows excellent agreement with reported experimental data.

Switches of hydrogen bonds during ligand-protein association processes determine binding kinetics.

Revealing the processes of ligand-protein associations deepens our understanding of molecular recognition and binding kinetics. Hydrogen bonds (H-bonds) play a crucial role in optimizing ligand-protein interactions and ligand specificity. In addition to the formation of stable H-bonds in the final bound state, the formation of transient H-bonds during binding processes contributes binding kinetics that define a ligand as a fast or slow binder, which also affects drug action.

The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides.

Solving the crystal structure of Cbl(TKB) in complex with a pentapeptide, pYTPEP, revealed that the PEP region adopted a poly-L-proline type II (PPII) helix. An unnatural amino acid termed a proline-templated glutamic acid (ptE) that constrained both the backbone and sidechain to the bound conformation was synthesized and incorporated into the pYTPXP peptide. We estimated imposing structural constraints onto the backbone and sidechain of the peptide and preorganize it to the bound conformation in solution will yield nearly an order of magnitude improvement in activity.

Mechanistic insights into phosphopeptide--BRCT domain association: preorganization, flexibility, and phosphate recognition.

Promiscuous proteins are commonly observed in biological systems, for example, in modular domains that recognize phosphopeptides during signal transduction. This promiscuous recognition is of fundamental interest in chemistry and biology but is challenging when designing phosphopeptides in silico for cell biology studies. To investigate promiscuous recognition and binding processes of phosphopeptides and the modular domain, we selected a domain essential in breast cancer-the breast-cancer-associated protein 1 (BRCA1) C-terminal (BRCT) repeats as our model system.

Gating and Intermolecular Interactions in Ligand-Protein Association: Coarse-Grained Modeling of HIV-1 Protease.

Most biological processes are initiated or mediated by the association of ligands and proteins. This work studies multistep, ligand-protein association processes by Brownian dynamics simulations with coarse-grained models for HIV-1 protease (HIVp) and its neutral ligands. We report the average association times when the ligand concentration is 100 μM.

A Pairwise Preferential Interaction Model for Understanding Peptide Aggregation.

A pairwise preferential interaction model (PPIM), based on Kirkwood-Buff integrals, is developed to quantify and characterize the interactions between some of the functional groups commonly observed in peptides. The existing experimental data are analyzed to determine the preferential interaction (PI) parameters for different amino acid and small peptide systems in aqueous solutions. The PIs between the different functional groups present in the peptides are then isolated and quantified by assuming simple pairwise additivity.

Comment on "Can existing models quantitatively describe the mixing behavior of acetone with water" [J. Chem. Phys. 130, 124516 (2009)].

A recent publication indicated that simulations of acetone-water mixtures using the KBFF model for acetone indicate demixing at mole fractions less than 0.28 of acetone, in disagreement with experiment and two previously published studies. Here, we indicate some inconsistancies in the current study which could help to explain these differences.

Direct observation of gold nanoparticle assemblies with the porin MspA on mica.

The octameric porin MspA from Mycobacterium smegmatis is sufficiently stable to form a nonmembrane-supported stand-alone porin on mica surfaces. About 98% of all MspA octamers were found to stand upright on mica, with their periplasmic loop regions bound to the hydrophilic mica surface. Both, small (d = 3.

Kirkwood-Buff theory of four and higher component mixtures.

Explicit expressions are developed for the chemical potential derivatives, partial molar volumes, and isothermal compressibility of solution mixtures involving four components at finite concentrations using the Kirkwood-Buff theory of solutions. In addition, a general recursion relationship is provided which can be used to generate the chemical potential derivatives for higher component solutions.

MspA Porin-Gold Nanoparticle Assemblies: Enhanced Binding through a Controlled Cysteine Mutation.

In this study, the interactions of two gold nanoparticles of different sizes (average diameters of 3.7 +/- 2.6 and 17 +/- 3 nm) with octameric mycobacterial porin A from Mycobacterium smegmatis (MspA) and a mutant of MspA featuring a cysteine mutation in position 126 (Q126C) are investigated.

Recent applications of Kirkwood-Buff theory to biological systems.

The effect of cosolvents on biomolecular equilibria has traditionally been rationalized using simple binding models. More recently, a renewed interest in the use of Kirkwood-Buff (KB) theory to analyze solution mixtures has provided new information on the effects of osmolytes and denaturants and their interactions with biomolecules. Here we review the status of KB theory as applied to biological systems.

A Kirkwood-Buff derived force field for amides.

A force field for the computer simulation of aqueous solutions of amides is presented. The force field is designed to reproduce the experimentally observed density and Kirkwood-Buff integrals for N-methylacetamide (NMA), allowing for an accurate description of the NMA activity. Other properties such as the translational diffusion constant and heat of mixing are also well reproduced.

Structure-activity relationships of simplified resiniferatoxin analogues with potent VR1 agonism elucidates an active conformation of RTX for VR1 binding.

We previously described a series of N-(3-acyloxy-2-benzylpropyl) homovanillate and N'-(4-hydroxy-3-methoxybenzyl) thiourea derivatives that were potent VR1 agonists with high-affinities and excellent analgesic profiles. The design of these simplified RTX analogues was based on our RTX-derived pharmacophore model which incorporates the 4-hydroxy-3-methoxyphenyl (A-region), C(20)-ester (B-region), orthophenyl (C1-region) and C(3)-keto (C2-region) groups of RTX. For the purpose of optimizing the spatial arrangement of the four principal pharmacophores on the lead agonists (1-4), we have modified the distances in the parent C-region, 3-acyloxy-2-benzylpropyl groups, by lengthening or shortening one carbon to vary the distances between the pharmacophores.

N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues: novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor.

Isosteric replacement of the phenolic hydroxyl group in potent vanilloid receptor (VR1) agonists with the alkylsulfonamido group provides a series of compounds which are effective antagonists to the action of the capsaicin on rat VR1 heterologously expressed in Chinese hamster ovary (CHO) cells. In particular, compound 61, N-[2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl]-N'-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea was a full antagonist against capsaicin, displayed a K(i) value of 7.8 nM (compared to 520 nM for capsazepine and 4 nM for 5-iodoRTX), and showed excellent analgesic activity in mice.