A holistic approach to bridge the gap between microsecond computer simulations and millisecond biological events

Introduction

Complete understanding of how complex biological objects operate and fulfill their cellular role requires at its core a detailed picture of the millisecond (ms) conformational transitions between functional states.

Challenges in Computational Investigation

Computational investigation of such ms-events is thwarted by our difficulty—and often impossibility—to identify and sample efficiently the relevant degrees of freedom at play. Additionally, there is a current limitation of all-atom molecular dynamics to the microsecond (μs) timescale on common computer architectures.

Proposed Approach

Guided by concrete biological questions that experiment alone has hitherto proven unable to address, we propose a holistic approach to bridge affordable μs-computer simulations and ms-biological processes without the aid of a special-purpose supercomputer.

Methodology

To meet this grand theoretical challenge, we will associate two powerful developments to make the quantum leap and open a breadth of applications, scaling up to very large biological objects, so far inaccessible to μs-timescale computer simulations:

1. Determining the Reaction Coordinate: We will determine the reaction coordinate in an unprecedented combination of data-driven discovery of collective variables and advanced algorithms to find the minimum free-energy pathway that connects the end states of the conformational transition.

2. Accelerating Sampling: We will accelerate sampling along this pathway by associating ergodic schemes to a novel approach that maps complex free-energy landscapes significantly faster than its competitors.

Application to V1Vo–ATPase

We will apply this methodology to a V1Vo–ATPase, a complete ATP-driven biological motor that converts over the ms-timescale the chemical energy of ATP hydrolysis into mechanical work, with minimalist dissipation.

Expected Outcomes

Beyond illuminating the allosteric pathways that underlie the conformational transition, an atomic-level description of the rotary-catalysis milestones will shed new light on the effects of pathological mutations altering ATP activity. This work will also help engineer artificial cells with accelerated ATP turnover.