Top-down Mesoscale Models and Free Energy Calculations of Multivalent Protein-Protein and Protein-Membrane Interactions in Nanocarrier Adhesion and Receptor Trafficking

Liu, Jin; Agrawal, Neeraj J.; Eckmann, David M.; Ayyaswamy, P. S.; Radhakrishnan, Ravi

doi:10.1039/9781849735049-00272

Cited by 4 publications

(5 citation statements)

References 104 publications

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“…Traditional multiscale modelling involves bottom‐up approaches of systematically coarse‐graining the atomistic description, in order to access the mesoscale [36]. Alternatively, a top‐down approach can be pursued, in which models are constructed at the mesoscale based on phenomenological interaction potentials, and the parameters are determined directly by independent biophysical experimentation [37]. In works published in the literature, both approaches have been extensively employed as viable avenues for pursuing models that provide physical insight as well as for enabling direct contact with experiments [17].…”

Section: Methodsmentioning

confidence: 99%

Multiscale computational models in physical systems biology of intracellular trafficking

Tourdot¹,

Bradley²,

Natesan³

et al. 2014

IET Systems Biology

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In intracellular trafficking, a definitive understanding of the interplay between protein binding and membrane morphology remains incomplete. The authors describe a computational approach by integrating coarse-grained molecular dynamics (CGMD) simulations with continuum Monte Carlo (CM) simulations of the membrane to study protein–membrane interactions and the ensuing membrane curvature. They relate the curvature field strength discerned from the molecular level to its effect at the cellular length-scale. They perform thermodynamic integration on the CM model to describe the free energy landscape of vesiculation in clathrin-mediated endocytosis. The method presented here delineates membrane morphologies and maps out the free energy changes associated with membrane remodeling due to varying coat sizes, coat curvature strengths, membrane bending rigidities, and tensions; furthermore several constraints on mechanisms underlying clathrin-mediated endocytosis have also been identified, Their CGMD simulations have revealed the importance of PIP2 for stable binding of proteins essential for curvature induction in the bilayer and have provided a molecular basis for the positive curvature induction by the epsin N-terminal homology (EIMTH) domain. Calculation of the free energy landscape for vesicle budding has identified the critical size and curvature strength of a clathrin coat required for nucleation and stabilisation of a mature vesicle.

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Section: Methodsmentioning

confidence: 99%

Multiscale computational models in physical systems biology of intracellular trafficking

Tourdot¹,

Bradley²,

Natesan³

et al. 2014

IET Systems Biology

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“…Hence, based on the afore-mentioned simulations and analysis of the continuum models, it is hypothesized that attractive interactions between curvature-inducing proteins can result from entropy of membrane undulations [261,[282][283][284] (the same phenomenon was investigated using particle-based simulations by Reynwar et al [166]). Using related continuum methods, preserving bidirectional coupling of protein-induced curvature migration and membrane undulations, the role of adhesive forces as well as anisotropy of curvature fields on membrane-mediated protein interactions have also been reported [260,[285][286][287][288]. The isotropic curvactants, described in section IV A, can be represented by the spontaneous curvature field C 0 , defined in the continuum model described by eqn.…”

Section: B Isotropic Curvature Modelsmentioning

confidence: 98%

Mesoscale computational studies of membrane bilayer remodeling by curvature-inducing proteins

Ramakrishnan,

Kumar,

Radhakrishnan

2015

Preprint

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Biological membranes constitute boundaries of cells and cell organelles. These membranes are soft fluid interfaces whose thermodynamic states are dictated by bending moduli, induced curvature fields, and thermal fluctuations. Recently, there has been a flood of experimental evidence highlighting active roles for these structures in many cellular processes ranging from trafficking of cargo to cell motility. It is believed that the local membrane curvature, which is continuously altered due to its interactions with myriad proteins and other macromolecules attached to its surface, holds the key to the emergent functionality in these cellular processes.Mechanisms at the atomic scale are dictated by protein-lipid interaction strength, lipid composition, lipid distribution in the vicinity of the protein, shape and amino acid composition of the protein, and its amino acid contents. The specificity of molecular interactions together with the cooperativity of multiple proteins induce and stabilize complex membrane shapes at the mesoscale. These shapes span a wide spectrum ranging from the spherical plasma membrane to the complex cisternae of the Golgi apparatus. Mapping the relation between the protein-induced deformations at the molecular scale and the resulting mesoscale morphologies is key to bridging cellular experiments across the various length scales. In this review, we focus on the theoretical and computational methods used to understand the phenomenology underlying protein-driven membrane remodeling. Interactions at the molecular scale can be computationally probed by all atom and coarse grained molecular dynamics (MD, CGMD), as well as dissipative particle dynamics (DPD) simulations, which we only describe in passing. We choose to focus on several continuum approaches extending the Canham -Helfrich elastic energy model for membranes to include the effect of curvature-inducing proteins and explore the conformational phase space of such systems. In this description, the protein is expressed in the form of a spontaneous curvature field. The approaches include field theoretical methods limited to the small deformation regime, triangulated surfaces and particle-based computational models to investigate the largedeformation regimes observed in the natural state of many biological membranes. Applications of these methods to understand the properties of biological membranes in homogeneous and inhomogeneous environments of proteins, whose underlying curvature fields are either isotropic or anisotropic, are discussed. The diversity in the curvature fields elicits a rich variety of morphological states, including tubes, discs, branched tubes, and caveola. Mapping the thermodynamic stability of these states as a function of tuning parameters such as concentration and strength of curvature induction of the proteins is discussed. The relative stabilities of these self-organized shapes are examined through free-energy calculations. The suite of methods discussed here can be tailored to applications in specific cellular setting...

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“…As an illustrative example, inspired by the framework in Ref. [63], a mesoscale model of NCs functionalized with antibodies which bind to antigens on the EC surface amid fluid flow and glycocalyx interactions has been developed, validated, and the absolute binding free energy has been computed [29,[64][65][66]. Specific computational methodology to reveal NC Brownian motion and relevant hydrodynamic interactions have been developed and validated [51][52][53]64,65], and this further expands both time and length scales involved for bridging the transit phase of NC motion in blood flow, subsequent near wall interactions and resultant binding at the target site.…”

Section: Introductionmentioning

confidence: 99%

“…Bridging techniques that seamlessly integrate two distinct length scales in this category include mixed quantum mechanics/molecular mechanics (QM/MM) [67], and integrated molecular mechanics/ coarse-grained or MM/CG approaches [68]. Alternatively, a topdown approach may be used, in which models are constructed at the mesoscale based on phenomenological interaction potentials, with specific choices of governing equations then validated by experiment [64]. Such methods involve continuum scale formalisms and often incorporate finer length scales by considering spatial heterogeneities as inhomogeneous fields [69].…”

Section: Introductionmentioning

confidence: 99%

Nanocarrier Hydrodynamics and Binding in Targeted Drug Delivery: Challenges in Numerical Modeling and Experimental Validation

Ayyaswamy

Muzykantov

Eckmann

et al. 2013

Journal of Nanotechnology in Engineering and Medicine

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This review discusses current progress and future challenges in the numerical modeling of targeted drug delivery using functionalized nanocarriers (NC). Antibody coated nanocarriers of various size and shapes, also called functionalized nanocarriers, are designed to be injected in the vasculature, whereby they undergo translational and rotational motion governed by hydrodynamic interaction with blood particulates as well as adhesive interactions mediated by the surface antibody binding to target antigens/receptors on cell surfaces. We review current multiscale modeling approaches rooted in computational fluid dynamics and nonequilibrium statistical mechanics to accurately resolve fluid, thermal, as well as adhesive interactions governing nanocarrier motion and their binding to endothelial cells lining the vasculature. We also outline current challenges and unresolved issues surrounding the modeling methods. Experimental approaches in pharmacology and bioengineering are discussed briefly from the perspective of model validation.

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Top-down Mesoscale Models and Free Energy Calculations of Multivalent Protein-Protein and Protein-Membrane Interactions in Nanocarrier Adhesion and Receptor Trafficking

Cited by 4 publications

References 104 publications

Multiscale computational models in physical systems biology of intracellular trafficking

Multiscale computational models in physical systems biology of intracellular trafficking

Mesoscale computational studies of membrane bilayer remodeling by curvature-inducing proteins

Nanocarrier Hydrodynamics and Binding in Targeted Drug Delivery: Challenges in Numerical Modeling and Experimental Validation

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