Mechanics and physics of HIV virus interaction with cell membranes

A key step in the HIV infection process is the fusion of the virion membrane with the target cell membrane and the concomitant transfer of the viral RNA. Experimental evidence appears to suggest that the fusion is preceded by considerable elastic softening and thinning of the cell membranes and the formation of well-defined pores. What are the precise mechanisms underpinning the elastic softening of the membrane upon peptide insertion? A clear understanding of this could potentially pave the way for intelligent drug design to combat the epidemic caused by this deadly virus. State-of-the-art experiments to understand the HIV peptide insertion with T-cell membranes have been conducted recently. Using diffuse X-ray scattering, they deduced the bending modulus of the membranes upon HIV fusion peptide addition. Depending on the type of membrane, they found that the bending modulus (i.e., the property which dictates how resistant a membrane is to mechanical bending) can reduce between 3 and 13 times. This enormous mechanical softening greatly facilitates the subsequent fusion and infection process. Although the experimental findings are quite interesting, very little atomistic insights were gleaned. In short, modeling or simulations are necessary to interpret the aforementioned experiments and then provide guidelines for computationally driven rationale drug design. Predicated on the hypothesis that understanding, at the atomistic level, the membrane softening due to HIV peptide insertion will enable countermeasures, we have conducted large-scale molecular dynamics simulations on the interaction between HIV fusion peptide and cell membrane. Such simulations require modeling millions of atoms that interact with each through a complicated set of forces. The dynamics of such an ensemble was then studied and interpreted. For example, although the experiments were able to measure the overall reduction in bending modulus of the membrane – upon interaction with the HIV peptide – the key physics lies in what is happening locally at the peptide–membrane insertion interface. What exactly happens there that causes an overall softening of the membrane? In principle, insertion of rigid proteins or peptide in membranes ought to stiffen the membrane not soften it thus rendering the experimental observations even more perplexing. To this end, we have devised a numerical “experiment” which involves (computationally) sticking a needle into the membrane region of interest. Through derived theoretical formulae, and observation of the response of the atoms in the simulation when subject to the needle probe, we estimated the elastic behavior of a small and local patch of the membrane as opposed to the entire membrane itself. This, and the direct observation of the atomic behavior, allowed us to understand precisely what occurs at the peptide–membrane interface

Mechanism underpinning biological ferroelectricity

Ferroelectricity in biological materials, while speculated, has been a matter of much debate. Recent experimental discovery of this phenomenon in elastin – a key ingredient of aorta, lung, ligament, and skin has given rise to tantalizing questions regarding its origins as well as ramifications. In this presentation, motivated by the experiments performed by one of us, we present a two-scale modeling approach consisting of a coarse-grained statistical mechanics model and molecular dynamics to elucidate the microscopic mechanisms underpinning ferroelectricity in elastin

Electromechanical Couplings in Soft Matter and Biology

The ability of certain materials to deform in response to an electrical field or, conversely, generate an electrical field due to mechanical stimuli has tantalizing implications in fields ranging from biology to engineering. Various forms of electromechanical (and related) couplings, e.g., piezoelectricity, pyroelectricity, Maxwell stress effect, and ferroelectricity among others, have found use in topics ranging from energy harvesting, soft robots, sensors, and artificial muscles to the understanding of biological phenomena like mammalian hearing. In this dissertation, using methods ranging from quantum mechanics based density functional theory, empirical force-field molecular dynamics, statistical mechanics and continuum mechanics, the following topics are addressed: (i) Anomalous piezoelectricity in two-dimensional graphene nitride nanosheets: Using quantum mechanical simulations and qualitative arguments from continuum mechanics, the mechanisms that lead to the development of unexpected piezoelectricity in this 2D material are elucidated. (ii) What is the mechanism behind biological ferroelectricity?: The first evidence of ferroelectricity in biological materials was recently discovered in 2012. Biological materials shown to be ferroelectric are largely composed of the protein elastin, a large biopolymer found in the extracellular domains of most tissues. A new model and an explanation for this intriguing observation are presented. Based on a relatively simple hypothesis, an analytical statistical mechanics model is developed which, coupled with insights from molecular dynamics, provides a plausible mechanism underpinning biological ferroelectricity. Furthermore, piezoelectric properties of tropoelastin, a precursor/monomer of elastin are predicted for the first time. Specifically, it is found that the piezoelectric constant of tropoelastin is larger than any known polymer. (iii) Mammalian hearing mechanism: The mechanisms underpinning the role of the ion channel Prestin in mammalian hearing are explored. The conductance of the Prestin channel is found via molecular dynamics, an important parameter for the derivation of an analytical model of the hearing mechanism. (iv) A novel approach to estimate Gaussian modulus and edge properties of lipid bilayers: The Gaussian modulus is a largely neglected parameter of membranes which is difficult to find. A model is derived to relate the properties of the free edge of a membrane to its fluctuations.Mechanical Engineering, Department o

A Computable Phenotype for Acute Respiratory Distress Syndrome Using Natural Language Processing and Machine Learning

Acute Respiratory Distress Syndrome (ARDS) is a syndrome of respiratory failure that may be identified using text from radiology reports. The objective of this study was to determine whether natural language processing (NLP) with machine learning performs better than a traditional keyword model for ARDS identification. Linguistic pre-processing of reports was performed and text features were inputs to machine learning classifiers tuned using 10-fold cross-validation on 80% of the sample size and tested in the remaining 20%. A cohort of 533 patients was evaluated, with a data corpus of 9,255 radiology reports. The traditional model had an accuracy of 67.3% (95% CI: 58.3-76.3) with a positive predictive value (PPV) of 41.7% (95% CI: 27.7-55.6). The best NLP model had an accuracy of 83.0% (95% CI: 75.9-90.2) with a PPV of 71.4% (95% CI: 52.1-90.8). A computable phenotype for ARDS with NLP may identify more cases than the traditional model

Poly-albumen: Bio-derived structural polymer from polymerized egg white

Bio-derived materials could play an important role in future sustainable green and health technologies. This work reports the synthesis of a unique egg white-based bio-derived material showing excellent stiffness and ductility by polymerizing it with primary amine-based chemical compounds to form strong covalent bonds. As shown by both experiments and theoretical simulations, the amine-based molecules introduce strong bonds between amine ends and carboxylic ends of albumen amino acids resulting in an elastic modulus of ∼4 GPa, a fracture strength of ∼2 MPa and a high ductility of 40%. The distributed and interconnected network of interfaces between the hard albumen and the soft amine compounds gives the structure its unique combination of high stiffness and plasticity. A range of in-situ local and bulk mechanical tests as well as molecular dynamics (MD) simulations, reveal a significant interfacial stretching during deformation and a micro-crack diversion leading to an increased in ductility and toughness. The structure also shows a self-stiffening behavior under dynamic loading and a strength-induced aging suggesting adaptive mechanical behavior. This egg white-derived material could also be developed for bio-compatible and bio-medical applications.by Peter Samora Owuor, Thierry Tsafack, Himani Agrawal, Hye Yoon Hwang, Matthew Zeliskob, Tong Lic, Sruthi Radhakrishnan, Jun Hyoung Park, Yingchao Yang, Anthony S. Stender, Sehmus Ozden, Jarin Joyner, Robert Vajtai, Benny A. Kaipparettu, Bingqing Wei, Jun Lou, Pradeep Sharma, Chandra Sekhar Tiwarya and Pulickel M. Ajaya