Cross-Talk between Overlap Interactions in Biomolecules: A Case Study of the β-Turn Motif

Noncovalent interactions play a pivotal role in regulating protein conformation, stability and dynamics. Among the quantum mechanical (QM) overlap-based noncovalent interactions, n→π* is the best understood with studies ranging from small molecules to β-turns of model proteins such as GB1. However, these investigations do not explore the interplay between multiple overlap interactions in contributing to local structure and stability. In this work, we identify and characterize all noncovalent overlap interactions in the β-turn, an important secondary structural element that facilitates the folding of a polypeptide chain. Invoking a QM framework of natural bond orbitals, we demonstrate the role of several additional interactions such as n→σ* and π→π* that are energetically comparable to or larger than n→π*. We find that these interactions are sensitive to changes in the side chain of the residues in the β-turn of GB1, suggesting that the n→π* may not be the only component in dictating β-turn conformation and stability. Furthermore, a database search of n→σ* and π→π* in the PDB reveals that they are prevalent in most proteins and have significant interaction energies (∼1 kcal/mol). This indicates that all overlap interactions must be taken into account to obtain a comprehensive picture of their contributions to protein structure and energetics. Lastly, based on the extent of QM overlaps and interaction energies, we propose geometric criteria using which these additional interactions can be efficiently tracked in broad database searches.

DNC4mC-Deep: Identification and Analysis of DNA N4-Methylcytosine Sites Based on Different Encoding Schemes By Using Deep Learning

N4-methylcytosine as one kind of modification of DNA has a critical role which alters genetic performance such as protein interactions, conformation, stability in DNA as well as the regulation of gene expression same cell developmental and genomic imprinting. Some different 4mC site identifiers have been proposed for various species. Herein, we proposed a computational model, DNC4mC-Deep, including six encoding techniques plus a deep learning model to predict 4mC sites in the genome of F. vesca, R. chinensis, and Cross-species dataset. It was demonstrated by the 10-fold cross-validation test to get superior performance. The DNC4mC-Deep obtained 0.829 and 0.929 of MCC on F. vesca and R. chinensis training dataset, respectively, and 0.814 on cross-species. This means the proposed method outperforms the state-of-the-art predictors at least 0.284 and 0.265 on F. vesca and R. chinensis training dataset in turn. Furthermore, the DNC4mC-Deep achieved 0.635 and 0.565 of MCC on F. vesca and R. chinensis independent dataset, respectively, and 0.562 on cross-species which shows it can achieve the best performance to predict 4mC sites as compared to the state-of-the-art predictor.

Insights into the Binding Mechanism of Ascorbic Acid and Violaxanthin with Violaxanthin De-Epoxidase (VDE) and Chlorophycean Violaxanthin De-Epoxidase (CVDE) Enzymes: Docking, Molecular Dynamics, and Free Energy Analysis

Photosynthetic organisms have evolved to work under low and high lights in photoprotection, acting as a scavenger of reactive oxygen species. The light dependent xanthophyll cycle involved in this process is performed by a key enzyme (present in the thylakoid lumen) Violaxanthin De-Epoxidase (VDE) in the presence of violaxanthin and ascorbic acid substrates. Phylogenetically, VDE is found to be connected with an ancestral enzyme Chlorophycean Violaxanthin De-Epoxidase (CVDE) present in the green algae on the stromal side of the thylakoid membrane. However, the structure and functions of CVDE were not known. In search of functional similarities involving this cycle, the structure, binding conformation, stability, and interaction mechanism of CVDE are explored with the two substrates in comparison to VDE. The structure of CVDE was determined by homology modeling and validated. In-silico docking (of first-principles-optimized substrates) revealed it has a larger catalytic domain than VDE. A thorough analysis of the binding affinity and stability of four enzyme-substrate complexes are performed by computing free energies and its decomposition, the root-mean-square deviation (RMSD) and fluctuation (RMSF), the radius of gyration, salt-bridge and hydrogen bonding interactions in molecular dynamics. Based on these, violaxanthin interacts with CVDE to the similar extent as that of VDE, hence its role is expected to be the same for both the enzymes. On the contrary, ascorbic acid has a weaker interaction with CVDE than VDE. As these interactions drive epoxidation or de-epoxidation process in the xanthophyll cycle, it immediately discerns that either ascorbic acid does not take part in de-epoxidation or this process requires a different cofactor because of the weaker interaction of ascorbic acid with CVDE in comparison to VDE.

Chronic wasting disease (CWD) prion strains evolve via adaptive diversification of conformers in hosts expressing prion protein polymorphisms

Chronic wasting disease (CWD) is caused by an unknown spectrum of prions and has become enzootic in populations of cervid species that express cellular prion protein (PrPC) molecules varying in amino acid composition. These PrPC polymorphisms can affect prion transmission, disease progression, neuropathology, and emergence of new prion strains, but the mechanistic steps in prion evolution are not understood. Here, using conformation-dependent immunoassay, conformation stability assay, and protein-misfolding cyclic amplification, we monitored the conformational and phenotypic characteristics of CWD prions passaged through deer and transgenic mice expressing different cervid PrPC polymorphisms. We observed that transmission through hosts with distinct PrPC sequences diversifies the PrPCWD conformations and causes a shift toward oligomers with defined structural organization, replication rate, and host range. When passaged in host environments that restrict prion replication, distinct co-existing PrPCWD conformers underwent competitive selection, stabilizing a new prion strain. Nonadaptive conformers exhibited unstable replication and accumulated only to low levels. These results suggest a continuously evolving diversity of CWD conformers and imply a critical interplay between CWD prion plasticity and PrPC polymorphisms during prion strain evolution.

In silico analysis of miR-137 transcription inhibition in homozygous (T/T) schizophrenic patients: a pilot study.

MicroRNA miR-137 single nucleotide polymorphism (rs1625579 SNP) is strongly associated with the worsening of schizophrenia symptoms and is involved in miR-137 gene suppression. MicroRNA miR-137 regulates synaptogenesis, neural plasticity and suppresses a variety of cancertypes. Based on in silico predictions of the current MIR137 Host Gene with and without the SNP, it can be hypothesized that the mutation reversibly inhibits miR-137 gene transcription by steric hindrance due to an alteration on DNA conformation, stability, electrostatic potential, and transcription factor binding sites.

In silico analysis of miR-137 transcription inhibition in homozygous (T/T) schizophrenic patients: a pilot study.

MicroRNA miR-137 single nucleotide polymorphism (rs1625579 SNP) is strongly associated with the worsening of schizophrenia symptoms and is involved in miR-137 gene suppression. MicroRNA miR-137 regulates synaptogenesis, neural plasticity and suppresses a variety of cancertypes. Based on in silico predictions of the current MIR137 Host Gene with and without the SNP, it can be hypothesized that the mutation reversibly inhibits miR-137 gene transcription by steric hindrance due to an alteration on DNA conformation, stability, electrostatic potential, and transcription factor binding sites.