Identifying vaccine escape sites via statistical comparisons of short-term molecular dynamics

Ferran

Mouli

et al. 2022

Preprint

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.

Section: Molecular Dynamic Simulation Protocolsmentioning

confidence: 99%

Section: Comparative Protein Dynamic and Statistical Analyses With Dr...mentioning

confidence: 99%

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

Ferran

Mouli

et al. 2022

Preprint

“…comparing the divergence of atom fluctuation between bound versus unbound protein states) [30–32]. We have applied this computational method to study of the evolution of emergent and endemic viral strains related to SARS-CoV-2 [33] and to the study of the evolution of antibody-binding escape mutations as well [34]. Here, we use this same comparative molecular dynamics-based approach to study individual amino acid sites involved in the binding of the various strains of the SARS-CoV-2 viral receptor-binding domain (RBD) to both the human and various Rhinolophus bat ACE2 orthologs (hACE2 and bACE2 resp.).…”

Section: Introductionmentioning

confidence: 99%

“…comparing the divergence of atom fluctuation between bound versus unbound protein states) [30][31][32]. We have applied this computational method to study of the evolution of emergent and endemic viral strains related to SARS-CoV-2 [33] and to the study of the evolution of antibody-binding escape mutations as well [34].…”

mentioning

confidence: 99%

Persistent cross-species SARS-CoV-2 variant infectivity predicted via comparative molecular dynamics simulation

Babbitt

2022

R. Soc. open sci.

Self Cite

Widespread human transmission of SARS-CoV-2 highlights the substantial public health, economic and societal consequences of virus spillover from wildlife and also presents a repeated risk of reverse spillovers back to naive wildlife populations. We employ comparative statistical analyses of a large set of short-term molecular dynamic (MD) simulations to investigate the potential human-to-bat (genus Rhinolophus ) cross-species infectivity allowed by the binding of SARS-CoV-2 receptor-binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2) across the bat progenitor strain and emerging human strain variants of concern (VOC). We statistically compare the dampening of atom motion across protein sites upon the formation of the RBD/ACE2 binding interface using various bat versus human target receptors (i.e. bACE2 and hACE2). We report that while the bat progenitor viral strain RaTG13 shows some pre-adaption binding to hACE2, it also exhibits stronger affinity to bACE2. While early emergent human strains and later VOCs exhibit robust binding to both hACE2 and bACE2, the delta and omicron variants exhibit evolutionary adaption of binding to hACE2. However, we conclude there is a still significant risk of mammalian cross-species infectivity of human VOCs during upcoming waves of infection as COVID-19 transitions from a pandemic to endemic status.

“…comparing the divergence of atom fluctuation between bound vs. unbound protein states) [30][31][32] and applied this to study of the evolution of emergent and endemic viral strains related to SARS-CoV-2 [33]. We have also recently applied this method to the study of the evolution of antibody binding escape mutations as well [34]. Here, we utilize this same comparative molecular dynamics-based approach to study of individual amino acid sites involved in the binding of the various strains of the SARS-CoV-2 viral receptor-binding domain (RBD) to both the human and Rhinolophus bat ACE2 orthologs (hACE2 and bACE2 resp.).…”

Section: Introductionmentioning

confidence: 99%

Persistent cross-species SARS-CoV-2 variant infectivity predicted via comparative molecular dynamics simulation

Babbitt

2022

Preprint

Self Cite

Widespread human transmission of SARS-CoV-2 highlights the substantial public health, economic, and societal consequences of virus spillover from wildlife and also presents a repeated risk of reverse spillovers back to naïve wildlife populations. We employ comparative statistical analyses of a large set of short-term molecular dynamic (MD) simulations to investigate potential human to bat (Rhinolophus macrotis) cross-species infectivity allowed by the binding of SARS-CoV-2 receptor-binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2) across the bat progenitor strain and emerging human strain variants of concern (VOC). We statistically compare the dampening of atom motion during binding across protein sites upon the formation of the RBD/ACE2 binding interface using bat vs. human target receptors (i.e. bACE2 and hACE2). We report that while the bat progenitor viral strain RaTG13 shows some pre-adaption to binding hACE2, it also exhibits stronger overall affinity to bACE2. However, while the early emergent human strains and later VOC’s exhibit robust binding to both hACE2 and bACE2, the delta and omicron variants exhibit evolutionary adaption of binding to hACE2. However, we conclude there is a still significant risk of mammalian cross-species infectivity of human VOC’s during upcoming waves of infection as COVID-19 transitions from a pandemic to endemic status.