Lipid-dependent conformational landscape of the ErbB2 growth factor receptor dimers

Altered lipid metabolism has been linked to cancer development and progression. Several roles have been attributed to the increased saturation and length of lipid acyl tails observed in tumors, but its effect on signaling receptors is still emerging. In this work, we have analyzed the lipid dependence of the ErbB2 growth factor receptor dimerization that plays an important role in the pathogenesis of breast cancer. We have performed coarse-grain ensemble molecular dynamics simulations to comprehensively sample the ErbB2 monomer-dimer association. Our results indicate a dynamic dimer state with a complex conformational landscape that is modulated with increasing lipid tail length. We resolve the native N-terminal "active" and C-terminal "inactive" conformations in all membrane compositions. However, the relative population of the N-terminal and C-terminal conformers is dependent on length of the saturated lipid tails. In short-tail membranes, additional non-specific dimers are observed which are reduced or absent in long-tailed bilayers. Our results indicate that the relative population as well as the structure of the dimer state is modulated by membrane composition. We have correlated these differences to local perturbations of the membrane around the receptor. Our work is an important step in characterizing ErbB dimers in healthy and diseased states and emphasize the importance of sampling lipid dynamics in understanding receptor association

Thermodynamic and kinetic characterization of transmembrane helix association

The transient dimerization of transmembrane proteins is an important event in several cellular processes and computational methods are being increasingly used to quantify their underlying energetics. Here, we probe the thermodynamics and kinetics of a simple transmembrane dimer to understand membrane protein association. A multi-step framework has been developed in which the dimerization profiles are calculated from coarse-grain molecular dynamics simulations, followed by meso-scale simulations using parameters calculated from the coarse-grain model. The calculated value of ΔGassoc is approx. −20 kJ mol−1 and is consistent between three methods. Interestingly, the meso-scale stochastic model reveals low dimer percentages at physiologically-relevant concentrations, despite a favorable ΔGassoc. We identify generic driving forces arising from the protein backbone and lipid bilayer and complementary factors, such as protein density, that govern self-interactions in membranes. Our results provide an important contribution in understanding membrane protein organization and linking molecular, nano-scale computational studies to meso-scale experimental data

TEQIP - III Sponsored First International Conference on Innovations and Challenges in Computing, Analytics and Security

This book contains abstracts of the various research papers of the academic & research community presented at the International Conference on Innovations and Challenges in Computing, Analytics and Security (ICICCAS-2020). ICICCAS-2020 has served as a platform for researchers, professionals to meet and exchange ideas on computing, data analytics, and security. The conference has invited papers in seven main tracks of Data Science, Networking Technologies, Sequential, Parallel, Distributed and Cloud Computing, Advances in Software Engineering, Multimedia, Image Processing, and Embedded Systems, Security and Privacy, Special Track (IoT, Smart Technologies and Green Engineering). The Technical and Advisory Committee Members were from various countries that have rich Research and Academic experience. Conference Title: TEQIP - III Sponsored First International Conference on Innovations and Challenges in Computing, Analytics and SecurityConference Acronym: ICICCAS-2020Conference Date: 29-30 July 2020Conference Location: Pondicherry Engineering College, Puducherry – 605014, India (Virtual Mode)Conference Organizer: Department of Computer Science and Engineering, Pondicherry Engineering College, Puducherry, India.Conference Sponsor: TEQIP-III NPIU (A Unit of the Ministry of Human Resource Development, India)