Explicit versus implicit consideration of binding partners in protein–protein complex to elucidate intrinsic dynamics

Abstract

Many proteins are involved in tightly controlled binding to other proteins by incorporating intrinsic dynamics in the binding process, which can in turn be modulated. Therefore, investigating the intrinsic dynamics of proteins is necessary to understand function in a comprehensive way. By intrinsic dynamics herein we mostly review the vibrational signature of a protein molecule popularly obtained from normal modes or essential modes. For normal modes one often considers that the molecule under investigation is a collection of springs in a solvent-free or implicit-solvent medium. However, in the context of a protein binding partner, the analysis of vibration of the target protein is often complicated due to molecular interaction within the complex. Generally, it is assumed that the isolated bound conformation of the target protein captures the implicit effect of the binding partner on the intrinsic dynamics, thereby any in uence of the partner molecule is also already integrated. Such an assumption allows large-scale studies of the conservation of protein exibility. However, in cases where a partner protein directly in uences vibration of a target via critical contacts at the protein-protein interface, the above assumption falls short of providing a detailed view. In this review, we discuss the implications of considering the dynamics of a protein in a protein-protein complex, as modelled implicitly and explicitly with methods dependent on elastic network models. We further propose how such an explicit consideration can be applied to understand critical protein-protein contacts that can be targeted in future studies. algorithm), some residue clusters using positive correlations (in black) and negative correlations (in pink) were identi ed. Corresponding clusters are shown in the context of bothstructures.

Exploring the conformational ensembles of protein-protein complex with transformer-based generative model

“…Accuracy ൌ TPାTN TPାTNାFPାFN (2) where TP is true positive, TN is true negative, FP is false positive, and FN is false negative.…”

“…Molecular dynamics (MD) simulations have wide applications for the conformations and dynamics of proteins and protein-protein complexes [2,3,14,[17][18][19]. MD samples from potential conformations of biomolecular systems to determine the most energetically favorable subspace in the conformational space.…”

“…Proteins are the basic components of life , and almost all proteins perform their functions through non-covalent interactions with proteins, peptides, nucleotides, and small molecules, and so on[1, 2]. Protein-protein interactions (PPIs) play a key role in many biological processes.…”

“…Training of deep generative models relies on conformations extracted from molecular dynamics simulations. Aims to learn the data distribution of molecular dynamics simulations is used to generate novel realistic ensembles of protein conformations[2, 4, 14].…”

Exploring the Conformational Ensembles of Protein–Protein Complex with Transformer-Based Generative Model

“…The aim to learn the data distribution of molecular dynamics simulations is used to generate novel realistic ensembles of protein conformations. 2,4,14 In this study, we proposed a Transformer-based generative framework to accelerate sampling and exploration of the conformational ensembles of protein−protein complexes. First, the crystal structure of the barnase−barstar complex was performed in 100 ns MD production simulations.…”