0000000000411678
AUTHOR
Adrien Nicolaï
Raman and Infrared Spectra of Acoustical, Functional Modes of Proteins from All-Atom and Coarse-Grained Normal Mode Analysis
The directions of the largest thermal fluctuations of the structure of a protein in its native state are the directions of its low-frequency modes (below 1 THz), named acoustical modes by analogy with the acoustical phonons of a material. The acoustical modes of a protein assist its conformational changes and are related to its biological functions. Low-frequency modes are difficult to detect experimentally. A survey of experimental data of low-frequency modes of proteins is presented. Theoretical approaches, based on normal mode analysis, are of first interest to understand the role of the acoustical modes in proteins. In this chapter, the fundamentals of normal mode analysis using all-ato…
Angstrom-Size Defect Creation and Ionic Transport through Pores in Single-Layer MoS2
Atomic-defect engineering in thin membranes provides opportunities for ionic and molecular filtration and analysis. While molecular-dynamics (MD) calculations have been used to model conductance through atomic vacancies, corresponding experiments are lacking. We create sub-nanometer vacancies in suspended single-layer molybdenum disulfide (MoS2) via Ga+ ion irradiation, producing membranes containing ∼300 to 1200 pores with average and maximum diameters of ∼0.5 and ∼1 nm, respectively. Vacancies exhibit missing Mo and S atoms, as shown by aberration-corrected scanning transmission electron microscopy (AC-STEM). The longitudinal acoustic band and defect-related photoluminescence were observe…
A Route toward Protein Sequencing using Solid-State Nanopores Assisted by Machine Learning
Solid-State Nanopores made of 2-D materials such as MoS2 have emerged as one of the most versatile sensors for single-biomolecule detection, which is essential for early disease diagnosis (biomarker detection). One of the most promising applications of SSN is DNA and protein sequencing, at a low cost and faster than the current standard methods. The detection principle relies on measuring the relatively small variations of ionic current as charged biomolecules immersed in an electrolyte traverse the nanopore, in response to an external voltage applied across the membrane. The passage of a biomolecule through the pore yields information about its structure and chemical properties, as demonst…
Human Inducible Hsp70: Structures, Dynamics, and Interdomain Communication from All-Atom Molecular Dynamics Simulations
The 70 kDa human heat shock protein is a major molecular chaperone involved in de novo folding of proteins in vivo and refolding of proteins under stress conditions. Hsp70 is related to several "misfolding diseases" and other major pathologies, such as cancer, and is a target for new therapies. Hsp70 is comprised of two main domains: an N-terminal nucleotide binding domain (NBD) and a C-terminal substrate protein binding domain (SBD). The chaperone function of Hsp70 is based on an allosteric mechanism. Binding of ATP in NBD decreases the affinity of the substrate for SBD, and hydrolysis of ATP is promoted by binding of polypeptide segments in the SBD. No complete structure of human Hsp70 is…
Decipher the mechanisms of protein conformational changes induced by nucleotide binding through free-energy landscape analysis: ATP binding to Hsp70.
ATP regulates the function of many proteins in the cell by transducing its binding and hydrolysis energies into protein conformational changes by mechanisms which are challenging to identify at the atomic scale. Based on molecular dynamics (MD) simulations, a method is proposed to analyze the structural changes induced by ATP binding to a protein by computing the effective free-energy landscape (FEL) of a subset of its coordinates along its amino-acid sequence. The method is applied to characterize the mechanism by which the binding of ATP to the nucleotide-binding domain (NBD) of Hsp70 propagates a signal to its substrate-binding domain (SBD). Unbiased MD simulations were performed for Hsp…
Conformational dynamics of full-length inducible human Hsp70 derived from microsecond molecular dynamics simulations in explicit solvent
Human 70 kDa heat shock protein (hHsp70) is an ATP-dependent chaperone and is currently an important target for developing new drugs in cancer therapy. Knowledge of the conformations of hHsp70 is central to understand the interactions between its nucleotide-binding domain (NBD) and substrate-binding domain (SBD) and is a prerequisite to design inhibitors. The conformations of ADP-bound (or nucleotide-free) hHsp70 and ATP-bound hHsp70 was investigated by using unbiased all-atom molecular dynamics (MD) simulations of homology models of hHsp70 in explicit solvent on a timescale of .5 and 2.7 μs, respectively. The conformational heterogeneity of hHsp70 was analyzed by computing effective free-e…
Curvature and Torsion of Protein Main Chain as Local Order Parameters of Protein Unfolding
International audience; Thermal protein unfolding resembles a global (two-state) phase transition. At the local scale, protein unfolding is, however, heterogeneous and probe dependent. Here, we consider local order parameters defined by the local curvature and torsion of the protein main chain. Because chemical shift (CS) measured by NMR spectroscopy is extremely sensitive to the local atomic environment, CS has served as a local probe of thermal unfolding of proteins by varying the position of the atomic isotope along the amino-acid sequence. The variation of the CS of each C(alpha) atom along the sequence as a function of the temperature defines a local heat-induced denaturation curve. We…