Quantitative Biology - Biomolecules Publications (50)

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Quantitative Biology - Biomolecules Publications

Herein (the first part of my work), I debunk the long-standing hypotheses that explain mitochondrial oxidative phosphorylation. Simple calculations point out that mitochondria are highly proton-deficient microcosms and therefore, elaborate proton pump machinery are not tenable. Further, other elements like the elaborate electron transport chain, chemiosmosis, rotary ATP synthesis, etc. Read More


Ribbons are topological objects of biological and technological importance. Here, we study the folding of thick ribbons with hydrophobic surfaces in a bad solvent in regimes in which either the ribbon's thickness or the solvent molecule size is not vanishingly small compared to the ribbon's width. Extensive Monte Carlo simulations show that ribbons of various lengths and with a small stiffness adopt several distinct configurations as the ground state that include rolled (Archimedean spiral), curled, twisted and globule conformations. Read More


We discuss the gauge field theory approach to protein structure study, which allows a natural way to introduce collective degrees of freedom and nonlinear topological structures. Local symmetry of proteins and its breaking in the medium is considered, what allows to derive Abelian Higgs model of protein backbone, correct folding of which is defined by gauge symmetry breaking due hydrophobic forces. Within this model structure of protein backbone is defined by superposition of one-dimensional topological solitons (kinks), what allows to reproduce the three-dimensional structure of the protein backbone with precision up to 1A and to predict its dynamics. Read More


Natural protein sequences contain a record of their history. A common constraint in a given protein family is the ability to fold to specific structures, and it has been shown possible to infer the main native ensemble by analyzing covariations in extant sequences. Still, many natural proteins that fold into the same structural topology show different stabilization energies, and these are often related to their physiological behavior. Read More


Native horse mucus is characterized with micro- and macrorheology and compared to hydroxyethylcellulose (HEC) gel as a model. Both systems show comparable viscoelastic properties on the microscale and for the HEC the macrorheology is in good agreement with the microrheology. For the mucus, the viscoelastic moduli on the macroscale are several orders of magnitude larger than on the microscale. Read More


A recent formulation of random-phase-approximation polymer theory for disordered protein phase separation is applied to investigate how the tendency for multiple chains of a protein to phase separate, as characterized by the critical temperature $T^*_{\rm cr}$, is related to the protein's single-chain average radius of gyration $\langle R_g\rangle$. For a set of thirty model sequences containing different permutations of an equal number of positively and negatively charged residues, we found a striking correlation $T^*_{\rm cr}\sim \langle R_g\rangle^{-\nu}$ with $\nu\approx 3.5$-$6. Read More


It is well-established that many physical properties of DNA at sufficiently long length scales can be understood by means of simple polymer models. One of the most widely used elasticity models for DNA is the twistable worm-like chain (TWLC), which describes the double helix as a continuous elastic rod with bending and torsional stiffness. An extension of the TWLC, which has recently received some attention, is the model by Marko and Siggia, who introduced an additional twist-bend coupling, expected to arise from the groove asymmetry. Read More


Background: It is necessary and essential to discovery protein function from the novel primary sequences. Wet lab experimental procedures are not only time-consuming, but also costly, so predicting protein structure and function reliably based only on amino acid sequence has significant value. TATA-binding protein (TBP) is a kind of DNA binding protein, which plays a key role in the transcription regulation. Read More


Many of the most important processes in cells take place on and across membranes. With the rise of an impressive array of powerful quantitative methods for characterizing these membranes, it is an opportune time to reflect on the structure and function of membranes from the point of view of biological numeracy. To that end, in this article, I review the quantitative parameters that characterize the mechanical, electrical and transport properties of membranes and carry out a number of corresponding order of magnitude estimates that help us understand the values of those parameters. Read More


Proteins have evolved to perform diverse cellular functions, from serving as reaction catalysts to coordinating cellular propagation and development. Frequently, proteins do not exert their full potential as monomers but rather undergo concerted interactions as either homo-oligomers or with other proteins as hetero-oligomers. The experimental study of such protein complexes and interactions has been arduous. Read More


In the course of evolution, proteins undergo important changes in their amino acid sequences, while their three-dimensional folded structure and their biological function remain remarkably conserved. Thanks to modern sequencing techniques, sequence data accumulate at unprecedented pace. This provides large sets of so-called homologous, i. Read More


The role of proton tunneling in biological catalysis remains an open question usually addressed with the tools of biochemistry. Here, we map the proton motion in a hydrogen-bonded system into a problem of pseudo-spins to allow us to approach the problem using quantum information theory and thermodynamics. We investigate the dynamics of the quantum correlations generated through two hydrogen bonds between a prototypical enzyme and a substrate, and discuss the possibility of utilizing these correlations as a resource in the catalytic power of the enzyme. Read More


Allosteric effects are often underlying the activity of proteins and elucidating generic design aspects and functional principles which are unique to allosteric phenomena represents a major challenge. Here an approach which consists in the in silico design of synthetic structures which, as the principal element of allostery, encode dynamical long-range coupling among two sites is presented. The structures are represented by elastic networks, similar to coarse-grained models of real proteins. Read More


Using state-of-the-art techniques combining imaging methods and high-throughput genomic mapping tools leaded to the significant progress in detailing chromosome architecture of various organisms. However, a gap still remains between the rapidly growing structural data on the chromosome folding and the large-scale genome organization. Could a part of information on the chromosome folding be obtained directly from underlying genomic DNA sequences abundantly stored in the databanks? To answer this question, we developed an original discrete double Fourier transform (DDFT). Read More


The key finding in the DNA double helix model is the specific pairing or binding between nucleotides A-T and C-G, and the pairing rules are the molecule basis of genetic code. Unfortunately, no such rules have been discovered for proteins. Here we show that similar rules and intrinsic sequence patterns between intra-protein binding peptide fragments do exist, and they can be extracted using a deep learning algorithm. Read More


Cytosine methylation has been found to play a crucial role in various biological processes, including a number of human diseases. The detection of this small modification remains challenging. In this work, we computationally explore the possibility of detecting methylated DNA strands through direct electrical conductance measurements. Read More


We review the status of protein-based molecular electronics. First we discuss fundamental concepts of electron transfer and transport in and across proteins and proposed mechanisms for these processes. We then describe the immobilization of proteins to solid-state surfaces in both nanoscale and macroscopic approaches, and highlight how different methodologies can alter protein electronic properties. Read More


Recently developed deep learning techniques have significantly improved the accuracy of various speech and image recognition systems. In this paper we show how to adapt some of these techniques to create a novel chained convolutional architecture with next-step conditioning for improving performance on protein sequence prediction problems. We explore its value by demonstrating its ability to improve performance on eight-class secondary structure prediction. Read More


PHAST is a software package written in standard Fortran, with MPI and CUDA extensions, able to efficiently perform parallel multicanonical Monte Carlo simulations of single or multiple heteropolymeric chains, as coarse-grained models for proteins. The outcome data can be straightforwardly analyzed within its microcanonical Statistical Thermodynamics module, which allows for computing the entropy, caloric curve, specific heat and free energies. As a case study, we investigate the aggregation of heteropolymers bioinspired on $A\beta_{25-33}$ fragments and their cross-seeding with $IAPP_{20-29}$ isoforms. Read More


The 70 kDa Heat Shock Proteins Hsp70 have several essential functions in living systems, such as protecting proteins against protein aggregation, assisting protein folding, remodeling protein complexes and driving the translocation into organelles. These functions require high affinity for non-specific amino-acid sequences that are ubiquitous in proteins. It has been recently shown that this high affinity, called ultra-affinity, depends on a process driven out of equilibrium by ATP hydrolysis. Read More


Emergence of antibiotic resistance due to New Delhi Metallo $\beta$-lactamase (NDM-1) bacterial enzymes is of great concern due to their ability to hydrolyze wide range of antibiotics. Efforts are ongoing to obtain the atomistic details of the hydrolysis mechanism in order to develop novel drugs and inhibitors against NDM-1. Especially, it remains elusive how drug molecules of different family of antibiotics are hydrolyzed by NDM-1 in an efficient manner. Read More


Ribonucleic acid (RNA) is involved in many regulatory and catalytic processes in the cell. The function of any RNA molecule is intimately related with its structure. In-line probing experiments provide valuable structural datasets for a variety of RNAs and are used to characterize conformational changes in riboswitches. Read More


Recent experiments have shown that trivalent ion, spermidine$^{3+}$, can provoke lateral microphase segregation in DNA brushes. Using molecular simulations and simple theoretical arguments, we explore the effects of trivalent counterions on polyelectrolyte brushes. At a proper range of grafting density, polymer size, and ion concentration, the brush polymers collapse heterogeneously into octopus-like surface micelles. Read More


The percentage and sequence of AT and GC base pairs and charges on the DNA backbone contribute significantly to the stiffness of DNA. This elastic property of DNA also changes with small interacting ligands. The single-molecule force spectroscopy technique shows different interaction modes by measuring the mechanical properties of DNA bound with small ligands. Read More


Free energy perturbation (FEP) is frequently used to evaluate the free energy change of a biological process, e.g. the drug binding free energy or the ligand solvation free energy. Read More


As high-throughput biological sequencing becomes faster and cheaper, the need to extract useful information from sequencing becomes ever more paramount, often limited by low-throughput experimental characterizations. For proteins, accurate prediction of their functions directly from their primary amino-acid sequences has been a long standing challenge. Here, machine learning using artificial recurrent neural networks (RNN) was applied towards classification of protein function directly from primary sequence without sequence alignment, heuristic scoring or feature engineering. Read More


Nonnative residual interactions have attracted increasing attention in recent protein folding researches. Experimental and theoretical investigations had been set out to catch nonnative contacts that might dominate key events in protein folding. However, energetic frustrations caused by nonnative inter-residue interactions are not systematically characterized, due to the complicated folding mechanism. Read More


Identifying protein functional sites (PFSs) and protein-ligand interactions (PLIs) are critically important in understanding the protein function and the involved biochemical reactions. As large amount of unknown proteins are quickly accumulated in this post-genome era, an urgent task arises to predict PFSs and PLIs at residual level. Nowadays many knowledge-based methods have been well developed for prediction of PFSs, however, accurate methods for PLI prediction are still lacking. Read More


Ordered chains (such as chains of amino acids) are ubiquitous in biological cells, and these chains perform specific functions contingent on the sequence of their components. Using the existence and general properties of such sequences as a theoretical motivation, we study the statistical physics of systems whose state space is defined by the possible permutations of an ordered list, i.e. Read More


Chemical or enzymatic cross-linking of casein micelles (CMs) increases their stability against dissociating agents. In this paper, a comparative study of stability between native CMs and CMs cross-linked with genipin (CMs-GP) as a function of pH is described. Stability to temperature and ethanol were investigated in the pH range 2. Read More


Using a structure-based coarse-grained model of proteins, we study the mechanism of unfolding of knotted proteins through heating. We find that the dominant mechanisms of unfolding depend on the temperature applied and are generally distinct from those identified for folding at its optimal temperature. In particular, for shallowly knotted proteins, folding usually involves formation of two loops whereas unfolding through high-temperature heating is dominated by untying of single loops. Read More


The rotary sequential hydrolysis of metabolic machine F1-ATPase is a prominent feature to reveal high coordination among multiple chemical sites on the stator F1 ring, which also contributes to tight coupling between the chemical reaction and central {\gamma}-shaft rotation. High-speed AFM experiments discovered that the sequential hydrolysis was maintained on the F1 ring even in the absence of the {\gamma} rotor. To explore how the intrinsic sequential performance arises, we computationally investigated essential inter-subunit couplings on the hexameric ring of mitochondrial and bacterial F1. Read More


The principles behind the computation of protein-ligand binding free energies by Monte Carlo integration are described in detail. The simulation provides gas-phase binding free energies that can be converted to aqueous energies by solvation corrections. The direct integration simulation has several characteristics beneficial to free-energy calculations. Read More


About half of human cancers show normal TP53 gene and aberrant overexpression of Mdm2 and/or MdmX. This fact promotes a promising cancer therapeutic strategy which targeting the interactions between p53 and Mdm2/MdmX. For developing the inhibitors to disrupt the p53-Mdm2/MdmX interactions, we systematically investigate structural and interaction characteristics of p53 and inhibitors with Mdm2 and MdmX from atomistic level by exploiting stochastic molecular dynamics simulations. Read More


Proteins are biological polymers that underlie all cellular functions. The first high-resolution protein structures were determined by x-ray crystallography in the 1960s. Since then, there has been continued interest in understanding and predicting protein structure and stability. Read More


The rapid expansion in the spectrum of two-dimensional (2D) materials has driven the efforts of research on the fabrication of 2D composites and heterostructures. Highly ordered structure of 2D materials provides an excellent platform for controlling the ultimate structure and properties of the composite material with precision. However, limited control over the structure of the adherent material and its interactions with highly ordered 2D materials results in defective composites with inferior performance. Read More


Trapping nanoscopic objects to observe their dynamic behaviour for extended periods of time is an ongoing quest. Particularly, sub-100nm transparent objects are hard to catch and most techniques rely on immobilisation or transient diffusion through a confocal laser focus. We present an Anti-Brownian ELectrokinetic trap (pioneered by A. Read More


We show how active transport of ions can be interpreted as an entropy facilitated process. In this interpretation, the pore geometry through which substrates are transported can give rise to a driving force. This gives a direct link between the geometry and the changes in Gibbs energy required. Read More


Sedimentation velocity analytical ultracentrifugation with fluorescence detection has emerged as a powerful method for the study of interacting systems of macromolecules. It combines picomolar sensitivity with high hydrodynamic resolution, and can be carried out with photoswitchable fluorophores for multi-component discrimination, to determine the stoichiometry, affinity, and shape of macromolecular complexes with dissociation equilibrium constants from picomolar to micromolar. A popular approach for data interpretation is the determination of the binding affinity by isotherms of weight-average sedimentation coefficients, sw. Read More


Understanding the operation of biological molecular motors, nanoscale machines that transduce electrochemical energy into mechanical work, is enhanced by bottom-up strategies to synthesize novel motors. Read More


Circular polarization spectroscopy has proven to be an indispensable tool in photosynthesis research and (bio)-molecular research in general. Oxygenic photosystems typically display an asymmetric Cotton effect around the chlorophyll absorbance maximum with a signal $\leq 1 \%$. In vegetation, these signals are the direct result of the chirality of the supramolecular aggregates. Read More


We investigate dynamical coupling between water and amino acid side-chain residues in solvation dynamics by selecting residues often used as natural probes, namely tryptophan, tyrosine and histidine, located at different positions on protein surface and having various degrees of solvent exposure. Such differently placed residues are found to exhibit different timescales of relaxation. The total solvation response, as measured by the probe is decomposed in terms of its interactions with (i) protein core, (ii) side-chain atoms and (iii) water molecules. Read More


Monitoring the kinetics and conformational dynamics of single enzymes is crucial in order to better understand their biological functions as these motions and structural dynamics are usually unsynchronized among the molecules. Detecting the enzyme-reactant interactions and associated conformational changes of the enzyme on a single molecule basis, however, remain as a challenge with established optical techniques due to the commonly required labeling of the reactants or the enzyme itself. The labeling process is usually non-trivial and the labels themselves might skew the physical properties of the enzyme. Read More


Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations are widely used in enzyme simulation. Over ten convergence studies of QM/MM methods have revealed over the past several years that key energetic and structural properties approach asymptotic limits with only very large (ca. 500-1000 atom) QM regions. Read More


Assuming that mutation and fixation processes are reversible Markov processes, we prove that the equilibrium ensemble of sequences obeys a Boltzmann distribution with $\exp(4N_e m (1 - 1/(2N)))$, where $m$ is a Malthusian fitness and $N_e$ and $N$ are the effective and actual population sizes. Combining this finding with the knowledge of protein folding, we derive a correspondence between protein fitness and folding free energy, i.e. Read More


The probability distribution of sequences with maximum entropy that satisfies a given amino acid composition at each site and a given pairwise amino acid frequency at each site pair is a Boltzmann distribution with $\exp(-\psi_N)$, where the total interaction $\psi_N$ is represented as the sum of one body and pairwise interactions. A protein folding theory based on the random energy model (REM) indicates that the equilibrium ensemble of natural protein sequences is a canonical ensemble characterized by $\exp(-\Delta G_{ND}/k_B T_s)$ or by $\exp(- G_{N}/k_B T_s)$ if an amino acid composition is kept constant, meaning $\psi_N = \Delta G_{ND}/k_B T_s +$ constant, where $\Delta G_{ND} \equiv G_N - G_D$, $G_N$ and $G_D$ are the native and denatured free energies, and $T_s$ is the effective temperature of natural selection. Here, we examine interaction changes ($\Delta \psi_N$) due to single nucleotide nonsynonymous mutations, and have found that the variance of their $\Delta \psi_N$ over all sites hardly depends on the $\psi_N$ of each homologous sequence, indicating that the variance of $\Delta G_N (= k_B T_s \Delta \psi_N)$ is nearly constant irrespective of protein families. Read More


Extensive molecular dynamics simulations reveal that the interactions between proteins and poly(ethylene glycol)(PEG) can be described in terms of the surface composition of the proteins. PEG molecules accumulate around non-polar residues while avoiding polar ones. A solvent-accessible-surface-area model of protein adsorption on PEGylated nanoparticles accurately fits a large set of data on the composition of the protein corona recently obtained by label-free proteomic mass spectrometry. Read More


Interaction with divalent cations is of paramount importance for RNA structural stability and function. We here report a detailed molecular dynamics study of all the possible binding sites for Mg$^{2+}$ on a RNA duplex, including both direct (inner sphere) and indirect (outer sphere) binding. In order to tackle sampling issues, we develop a modified version of bias-exchange metadynamics which allows us to simultaneously compute affinities with previously unreported statistical accuracy. Read More


Efficient replication and assembly of virus particles are integral to the establishment of infection. In addition to the primary role of the capsid protein (CP) in encapsidating the RNA progeny, experimental evidence on positive sense single-stranded RNA viruses suggests that the CP also regulates RNA synthesis. Here, we demonstrate that replication of Satellite tobacco mosaic virus (STMV) is controlled by the cooperative interaction between STMV CP and the helper virus (HV) Tobacco mosaic virus (TMV) replicase. Read More


In this paper, we introduce multiscale persistent functions for biomolecular structure characterization. The essential idea is to combine our multiscale rigidity functions with persistent homology analysis, so as to construct a series of multiscale persistent functions, particularly multiscale persistent entropies, for structure characterization. To clarify the fundamental idea of our method, the multiscale persistent entropy model is discussed in great detail. Read More