Improvements in the description of amino acid substitution are required to develop better pseudo‐energy‐based protein structure‐aware models for use in phylogenetic studies. These models are used to characterize the probabilities of amino acid substitution and enable better simulation of protein sequences over a phylogeny. A better characterization of amino acid substitution probabilities in turn enables numerous downstream applications, like detecting positive selection, ancestral sequence reconstruction, and evolutionarily‐motivated protein engineering. Many existing Markov models for amino acid substitution in molecular evolution disregard molecular structure and describe the amino acid substitution process over longer evolutionary periods poorly. Here, we present a new model upgraded with a site‐specific parameterization of pseudo‐energy terms in a coarse‐grained force field, which describes local heterogeneity in physical constraints on amino acid substitution better than a previous pseudo‐energy‐based model with minimum cost in runtime. The importance of each weight term parameterization in characterizing underlying features of the site, including contact number, solvent accessibility, and secondary structural elements was evaluated, returning both expected and biologically reasonable relationships between model parameters. This results in the acceptance of proposed amino acid substitutions that more closely resemble those observed site‐specific frequencies in gene family alignments. The modular site‐specific pseudo‐energy function is made available for download through the following website:
Proteins are the active players in performing essential molecular activities throughout biology, and their dynamics has been broadly demonstrated to relate to their mechanisms. The intrinsic fluctuations have often been used to represent their dynamics and then compared to the experimental B‐factors. However, proteins do not move in a vacuum and their motions are modulated by solvent that can impose forces on the structure. In this paper, we introduce a new structural concept, which has been called the structural compliance, for the evaluation of the global and local deformability of the protein structure in response to intramolecular and solvent forces. Based on the application of pairwise pulling forces to a protein elastic network, this structural quantity has been computed and sometimes is even found to yield an improved correlation with the experimental B‐factors, meaning that it may serve as a better metric for protein flexibility. The inverse of structural compliance, namely the structural stiffness, has also been defined, which shows a clear anticorrelation with the experimental data. Although the present applications are made to proteins, this approach can also be applied to other biomolecular structures such as RNA. This present study considers only elastic network models, but the approach could be applied further to conventional atomic molecular dynamics. Compliance is found to have a slightly better agreement with the experimental B‐factors, perhaps reflecting its bias toward the effects of local perturbations, in contrast to mean square fluctuations. The code for calculating protein compliance and stiffness is freely accessible at
- Award ID(s):
- 1661391
- NSF-PAR ID:
- 10456814
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Proteins: Structure, Function, and Bioinformatics
- Volume:
- 88
- Issue:
- 11
- ISSN:
- 0887-3585
- Page Range / eLocation ID:
- p. 1482-1492
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Rate and state frictional parameters are typically determined using two types of experimental protocols: velocity steps and slide‐hold‐slide events. Here we take a new approach by examining the frictional response to controlled, harmonic oscillations in load point velocity. We present a Matlab graphical user interface software package, called RSFitOSC, that allows users to easily determine frictional parameters by fitting oscillation events using the rate and state friction equations. We apply our new methods to a set of ice‐rock friction experiments conducted over a temperature range of −16.4°C to −2°C, and described in a companion paper: McCarthy et al. (2021,
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