Mouli, L. T. | Search bioRxiv

bioRxiv2023

ATOMDANCE: interpretable kernel-based learning for denoising functional and evolutionary comparisons of protein dynamics

Comparative methods in molecular biology and molecular evolution rely exclusively upon the analysis of DNA sequence and protein structure, both static forms of information. However, it is widely accepted that protein function results from changes in dynamic machine-like motions induced by molecular interactions, a type of data for which comparative methods of analysis are challenged by the large fraction of protein motion created by random thermal noise in the surrounding solvent. Here, we introduce ATOMDANCE, a suite of statistical and kernel-based machine learning tools designed for comparing and denoising functional states of protein motion captured in time-series from molecular dynamics simulations. ATOMDANCE employs interpretable Gaussian kernel functions to compute site-wise maximum mean discrepancy (MMD) between learned features of motion representing two functional, malfunctional or evolutionary protein states (e.g. bound vs. unbound, wild-type vs. mutant). ATOMDANCE derives empirical p-values identifying functional similarity/difference in dynamics at each amino acid site on the protein. ATOMDANCE also employs MMD to contextually analyze potential random amino-acid replacements thus allowing for a site-wise test of neutral vs. non-neutral evolution in the divergence of dynamic function in protein homologs. Lastly, ATOMDANCE also employs mixed-model ANOVA combined with graph network community detection to identify functional shifts in protein regions that exhibit time-coordinated dynamics or resonance of motion across sites. Here, we demonstrate the utility of the software for identifying key sites involved in dynamic responses during functional binding interactions involving DNA, small molecule drugs, and virus-host recognition. We also demonstrate its utility in understanding dynamic resonance changes occurring during the allosteric activation of a pathogenic protease. ATOMDANCE offers a user-friendly interface and only requires an input structure, topology and trajectory files for each of the two proteins being compared (i.e .pdb, .prmtop, and .nc). A separate interface for generating molecular dynamics simulations via open-source tools is also offered. Lay Audience Summary - ATOMDANCE is a suite of software pipelines controlled by a single user interface and designed to comprehensively simulate, calculate and compare protein motions between two functional or evolutionary states while controlling for random noise. It is useful for finding amino acid sites on a given protein that are important in binding other proteins, DNA, or drugs/toxins. It can also be used to assess the effect of genetic mutation on protein motion, and identifies regions of sites on proteins that tend to move together or resonate as a whole unit or community.

biophysics↗

bioRxiv2022

Evolution of drug resistance drives progressive destabilizations in functionally conserved molecular dynamics of the flap region of the HIV-1 protease

The HIV-1 protease is one of several common key targets of combination drug therapies for human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS). During the progression of the disease, some individual patients acquire -drug resistance due to mutational hotspots on the viral proteins targeted by combination drug therapies. It has recently been discovered that drug-resistant mutations accumulate on the flap region of the HIV-1 protease, which is a critical dynamic region involved in non-specific polypeptide binding during invasion and infection of the host cell. In this study, we utilize machine learning assisted comparative molecular dynamics, conducted at single amino acid site resolution, to investigate the dynamic changes that occur during functional dimerization and polypeptide binding of the main protease. We use a multi-agent machine learning model to identify conserved dynamics of the HIV-1 main protease that are preserved across simian and feline protease orthologs (SIV and FIV). We also investigate changes in dynamics due to common drug-resistant mutations in many patients. We find that a key functional site in the flap region, a solvent-exposed isoleucine (ILE50) and surrounding sites that control flap dynamics is often targeted by drug-resistance mutations, likely leading to malfunctional molecular dynamics affecting the overall flexibility of the flap region. We conclude that better long term patient outcomes may be achieved by designing drugs that target protease regions which are less dependent upon single sites with large functional binding effects.

bioinformatics↗