Computer simulations identify new ways to boost the skin’s natural protectors

Working with Unilever and the UK’s STFC Hartree Centre, IBM Research uncovered how skin can boost its natural defense against germs.

As reported in Biophysical Journal, small-molecule additives can enhance the potency of naturally occurring defense peptides. Molecular mechanisms responsible for this amplification were discovered using advanced simulation methods, in combination with experimental studies from Unilever.

When in balance, our skin and its microbiome form a natural partnership that helps to keep our skin healthy and defends against external threats, like pollutants and germs that can cause infections. Disturbances in that partnership (called dysbioses) can lead to imbalances in the microbiome which can also contribute to body odor, skin problems, and in more extreme cases, even lead to medical conditions like eczema (or atopic dermatitis).

In addition to hosting your microbiome, your skin is an immunologically active organ, contributing to your body’s innate immune system with its naturally mildly acidic pH, mechanical strength, lipids, and a natural release by skin cells of protein-like materials called antimicrobial peptides (AMPs). Together, these form the first line of defense against infection causing microbes that land on your skin.

Unilever R&D and its global network of research partners have been investigating the role of skin immunity and AMPs for over a decade. When Unilever needed to develop new ways to understand, at the molecular level, how its products interact with AMPs to enhance skin defense activity, the company turned to IBM Research.

IBM and Unilever — in collaboration with STFC, which hosts one of IBM Research’s Discovery Accelerators at the Hartree Centre in the UK — used high performance computing and advanced simulations running on IBM Power10 processors to understand how AMPs work and translate this knowledge into consumer products that boost the effects of these natural-defense peptides. This work builds upon a long-standing partnership between IBM, Unilever and the STFC Hartree Centre aimed at advancing digital research and innovation.

As we report in Biophysical Journal, our work alongside STFC’s Scientific Computing Department found that small-molecule additives (organic compounds with low molecular weights) can enhance the potency of these naturally occurring defense peptides. Using our own advanced simulation methods, in combination with experimental studies from Unilever, we also identified specific new molecular mechanisms that could be responsible for this improved potency.

Simulating molecular interactions

Although there’s been a lot of research focused on designing new, artificial antimicrobials, Unilever wanted to concentrate on boosting the potency of the body’s naturally occurring germ fighters with small-molecule additives. IBM Research has already developed computational models for membrane disruption and permeation through physical modeling, but Unilever’s challenge was a new area of exploration for us, given the extremely complex nature of having to model how AMPs interact with the skin and calculate which would be the most efficacious.

Several years ago, Unilever scientists in India discovered that Niacinamide, an active form of vitamin B3 naturally found in your skin and body, could enhance AMP expression levels in laboratory models. At the same time Unilever’s team also observed an unexpected enhancement of AMP antimicrobial activity in cell-free systems, and wanting to understand why this enhanced activity was happening — a research collaboration between Unilever, IBM, and STFC was initiated.

To answer Unilever’s question we developed computer simulations to investigate how single molecules interact with bacterial membranes at the molecular scale to demonstrate the fundamental biophysical mechanisms in play. These models then formed the basis of more complex simulations that examined in similar detail how small molecules interact with skin defense peptides to affect their potency. The results of these simulations were compared to the results of extensive laboratory experimental tests conducted by Unilever to confirm our computational predictions on a range of niacinamide analogs with differing abilities to promote AMP activity in lab models.

We first used physical modeling to determine the effects of the B3 analogs on LL37, a common AMP on human skin. We then simulated these molecules using high-performance computing to predict their performance and generate detailed time-bound simulations that allowed us to “see” these interactions in molecular detail. This work enabled us to demonstrate that niacinamide (and another analog, methyl niacinamide) could indeed naturally boost the effect of the AMP peptide LL37 on the bacterium Staphylococcus aureus, an organism widely associated with skin infections.

A radical discovery process — and a map for hunting new bioactives

Our work has helped us understand how these molecules can improve hygiene, but it also provided us with a deeper understanding of the molecular mechanisms responsible for enhanced AMP performance, by pairing simplified model systems and advanced computation that radically accelerated technology evaluation. We believe this workflow can allow us to create innovative and sustainable products that can help to protect us from pathogens both now and in the future.

The scientific method, applied to peptides.

This research was made possible by our and our partners’ capabilities in high-performance computing. Combining these technologies allowed us to supercharge the scientific method to promote discovery at a far more rapid pace, a process we’ve come to call accelerated discovery. 

We’re excited that our work can help Unilever better understand how to leverage AMPs in future products to help countless people around the world through the development of effective and sustainable hygiene products, while complying with the applicable regulations..

For us at IBM, this work is also the start of an exciting new chapter as we explore how this work can help accelerate research into other harmful pathogens, such as Methicillin-resistant Staphylococcus aureus (MRSA), that can cause severe disease if their growth is not controlled. More broadly, this work opens a new pathway to discovering natural, small-molecule boosters to amplify the function of antimicrobial peptides Our understanding of these mechanisms and the process we used can be applied for other research, for example, in the search for novel antimicrobials.

This was a cross-industry academia partnership that spanned the globe, with scientists from India and the UK coming together to solve germane and pressing problems with real world application. We hope one of the lasting impacts of this work is that for future research in this field, we’re able to choose or devise computational models simple enough to capture essential biological processes — without adding unnecessary time or complexity.

Source: ibm.com